U.S. patent number 5,494,928 [Application Number 08/317,259] was granted by the patent office on 1996-02-27 for indole derivatives.
This patent grant is currently assigned to Hoffmann-La Roche Inc.. Invention is credited to Michael Bos.
United States Patent |
5,494,928 |
Bos |
February 27, 1996 |
Indole derivatives
Abstract
The invention releates to indole derivatives of the formula
##STR1## wherein R.sup.1 to R.sup.4 are, independently, hydrogen,
halogen, lower-alkyl, cycloalkyl or trifluoromethyl, R.sup.5 and
R.sup.6 are, independently, hydrogen, halogen, lower-alkyl,
cycloalkyl, trifluoromethyl, hydroxy or lower-alkoxy and R.sup.7 is
hydrogen or lower-alkyl, and pharmaceutically acceptable acid
addition salts thereof. The compounds of formula I bind to
serotonin receptors and are therefore useful in the treatment
and/or prevention of central nervous system disorders, such as
depression.
Inventors: |
Bos; Michael (Rheinfelden,
CH) |
Assignee: |
Hoffmann-La Roche Inc. (Nutley,
NJ)
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Family
ID: |
4250849 |
Appl.
No.: |
08/317,259 |
Filed: |
October 3, 1994 |
Foreign Application Priority Data
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Oct 22, 1993 [CH] |
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3201/93 |
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Current U.S.
Class: |
514/415; 548/486;
548/484; 548/469; 514/418; 548/485 |
Current CPC
Class: |
A61P
25/18 (20180101); A61P 25/24 (20180101); A61P
43/00 (20180101); A61P 25/26 (20180101); A61P
25/28 (20180101); C07D 209/36 (20130101); A61P
9/00 (20180101); A61P 7/02 (20180101); A61P
25/20 (20180101); C07D 209/08 (20130101); A61P
25/06 (20180101); A61P 9/12 (20180101); A61P
1/00 (20180101); A61P 25/00 (20180101) |
Current International
Class: |
C07D
209/00 (20060101); C07D 209/36 (20060101); C07D
209/08 (20060101); A61K 031/40 (); C07D
209/04 () |
Field of
Search: |
;548/469,484,485,486
;514/415,418 |
Foreign Patent Documents
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2097465 |
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Jun 1993 |
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CA |
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0572863 |
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Aug 1993 |
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EP |
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Other References
CA 97:92759h Amino . . . Use. Geiger et al., p. 819, 1982. .
CA 66:94861u 2-Aminoethylation . . . -Indole. Pfeil et al., p.
8874, 1967. .
CA 102: 149796w N-Alkylated . . . Esters. Henning et al., p. 664,
1985. .
CA 109: 38242n Preparation . . . Senescence. Vincent et al., p.
660, 1988. .
CA 110:185342u Molecular . . . Recognition. Hadzi et al., p. 17,
1989. .
CA 112:199014s Molecular . . . Recognition. Hadzi et al., p. 780,
1990. .
J. Het. Chem. 16, 221-224 (1979). .
Proc. Roy. Soc. London, 148B, 481-494 (1958). .
Bull. Soc. Chim. France, 1978, 651. .
S. J. Peroutka, Biol. Psychiatry, 20 971-979 (1985). .
A. Pazos et al., Europ. J. Pharmacol. 106, 539-546 (1984). .
D. Hoyer, Receptor Research 8, 59-81 (1988). .
J. E. Leysen, Molecular Pharmacology 21, 301-314 (1981). .
S. J. Peroutka e al., Brain Research 584, 191-196 (1992). .
T. Branchek et al., Molecular Pharmacology 38, 604-609 (1990).
.
Berendensen & Broekkamp, Eur. J. Pharmacol. 135, 279-287
(1987). .
Knitel, Synthesis p. 186 (1985)..
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Primary Examiner: McKane; Joseph K.
Attorney, Agent or Firm: Gould; George M. Esptein; William
H. Semionow; Raina
Claims
I claim:
1. A compound of the formula ##STR13## wherein R.sup.1 to R.sup.4
are, independently, hydrogen, halogen, lower-alkyl, cycloalkyl or
trifluoromethyl, R.sup.5 and R.sup.6 are, independently, hydrogen,
halogen, lower-alkyl, cycloalkyl, trifluoromethyl, hydroxy or
lower-alkoxy and R.sup.7 is lower-alkyl,
or a pharmaceutically acceptable acid addition salt thereof.
2. A compound according to claim 1, wherein R.sup.7 is methyl.
3. A compound according to claim 1, wherein R.sup.5 and R.sup.6 are
hydrogen.
4. A compound according to claim 3, wherein R.sup.1 is hydrogen or
methyl, R.sup.2 is hydrogen or fluorine, R.sup.3 is hydrogen or
chlorine and R.sup.4 is hydrogen.
5. A compound selected from the group consisting of
(RS)-2-(5-Chloro-indol-1-yl)-1-methyl-ethylamine,
(RS)-2-(5-fluoro-indol-1-yl)-1-methyl-ethylamine,
(RS)-2-(6-chloro-5-fluoro-indol-1-yl)-1-methyl-ethylamine,
(R)-2-(5-fluoro-indol-1-yl)-1-methyl-ethylamine,
(S)-2-(6-chloro-5-fluoro-indol-1-yl)-1-methyl-ethylamine,
(R)-2-(6-chloro-5-fluoro-indol-1-yl)-1-methyl-ethylamine,
(RS)-2-(4-methyl-indol-1-yl)-1-methyl-ethylamine,
(RS)-2-(5-bromo-indol-1-yl)-1-methyl-ethylamine,
(RS)-2-(6-fluoro-indol-1-yl)-1-methyl-ethylamine,
(S)-2-(5,6-difluoro-indol-1-yl)-1-methyl-ethylamine,
(R)-2-(5,6-difluoro-indol-1-yl)-1-methyl-ethylamine,
(S)-2-(5-fluoro-4-trifluoromethyl-indol-1-yl)-1-methyl-ethylamine,
(S)-2-(5-fluoro-6-trifluoromethyl-indol-1-yl)-1-methyl-ethylamine,
(S)-2-(4-chloro-5-fluoro-indol-1-yl)-1-methyl-ethylamine, and
(R)-2-(4-chloro-5-fluoro-indol-1-yl)- i-methyl-ethylamine.
6. A pharmaceutical composition comprising an effective amount of a
compound of the formula ##STR14## wherein R.sup.1 to R.sup.4 are,
independently, hydrogen, halogen, lower-alkyl, cycloalkyl or
trifluoromethyl, R.sup.5 and R.sup.6 are, independently, hydrogen,
halogen, lower-alkyl, cycloalkyl, trifluoromethyl, hydroxy or
lower-alkoxy and R.sup.7 is lower-alkyl,
or a pharmaceutically acceptable acid addition salt thereof and an
inert carrier.
7. A method for blocking serotonin receptors in a host requiring
such treatment which comprises administering an effective amount of
a compound selected from the group consisting of ##STR15## wherein
R.sup.1 to R.sup.4 are, independently, hydrogen, halogen,
lower-alkyl, cycloalkyl or trifluoromethyl, R.sup.5 and R.sup.6
are, independently, hydrogen, halogen, lower-alkyl, cycloalkyl,
trifluoromethyl, hydroxy or lower-alkoxy and R.sup.7 is
lower-alkyl,
or a pharmaceutically acceptable acid addition salt thereof.
Description
SUMMARY OF THE INVENTION
The invention relates to indole derivatives of the formula ##STR2##
wherein R.sup.1 to R.sup.4 are, independently, hydrogen, halogen,
lower-alkyl, cycloalkyl or trifluoromethyl, R.sup.5 and R.sup.6
are, independently, hydrogen, halogen, lower-alkyl, cycloalkyl,
trifluoromethyl, hydroxy or lower-alkoxy and R.sup.7 is hydrogen or
lower-alkyl, and
pharmaceutically acceptable acid addition salts of the compounds of
formula I.
The compounds of formula I and their salts are distinguished by
valuable therapeutic properties.
In particular, the compounds of formula I are useful for the
treatment or prevention of central nervous disorders, such as,
depression. The compounds of formula I can also be used for the
treatment of bipolar disorders, anxiety states, sleep and sexual
disorders, psychoses, schizophrenia, migraine and other conditions
associated with cephalic pain or pain of a different kind,
personality disorders or obsessive-compulsive disorders, social
phobias or panic states, mental organic disorders, mental disorders
in childhood, aggressiveness, age-associated memory impairment and
behavioral disorders, addiction, obesity, bulimia and the like;
central nervous system damage caused by trauma, stroke,
neurodegenerative diseases and the like; and cardiovascular
disorders, such as, hypertension, thrombosis, stroke, and
gastrointestinal disorders, such as, dysfunction of the
gastrointestinal tract motility.
In another aspect, the invention relates to compounds of the
formula ##STR3## wherein R.sup.1 to R.sup.7 have the significance
given above and R.sup.8 is a residue convertible Into an amino
group, a leaving group or a hydroxy group.
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to indole derivatives of the formula ##STR4##
wherein R.sup.1 to R.sup.4 are, independently, hydrogen, halogen,
lower-alkyl, cycloalkyl or trifiuoromethyl, R.sup.5 and R.sup.6
are, independently, hydrogen, halogen, lower-alkyl, cycloalkyl,
trifluoromethyl, hydroxy or lower-alkoxy and R.sup.7 is hydrogen or
lower-alkyl, and
pharmaceutically acceptable acid addition salts of the compounds of
formula I.
In particular, the compounds of formula I are useful for the
treatment or prevention of central nervous disorders, such as,
depression. The compounds of formula I can also be used for the
treatment of bipolar disorders, anxiety states, sleep and sexual
disorders, psychoses, schizophrenia, migraine and other conditions
associated with cephalic pain or pain of a different kind,
personality disorders or obsessive-compulsive disorders, social
phobias or panic states, mental organic disorders, mental disorders
in childhood, aggressiveness, age-associated memory impairment and
behavioral disorders, addiction, obesity, bulimia and the like;
central nervous system damage caused by trauma, stroke,
neurodegenerative diseases and the like; and cardiovascular
disorders, such as, hypertension, thrombosis, stroke, and
gastrointestinal disorders, such as, dysfunction of the
gastrointestinal tract motility.
Objects of the invention are the compounds of formula I and
pharmaceutically acceptable acid addition salts thereof, the
preparation of the compounds of formula I and salts thereof,
medicaments containing a compound of formula I or a as
pharmaceutically acceptable acid addition salt thereof, the
manufacture of such medicaments and the use of the compounds of
formula I and their pharmaceutically acceptable salts in the
control or prevention of illnesses, especially of illnesses and
disorders of the kind referred to earlier, and, respectively, for
the manufacture of corresponding medicaments.
Furthermore, the invention also relates to the compounds of the
formula: ##STR5## wherein R.sup.1 to R.sup.7 have the significance
given above and R.sup.8 is a residue convertible into an amino
group, a leaving group or a hydroxy group.
These compounds of formula II are important intermediates for the
preparation of the pharmaceutically valuable compounds of formula
I.
The term "lower" denotes residues with a maximum of 7, preferably
up to 4, carbon atoms; "alkyl" denotes straight-chain or branched,
saturated hydrocarbon residues, such as, methyl, ethyl, isopropyl
or t-butyl; and alkoxy denotes an alkyl group bonded via an oxygen
atom, such as methoxy, ethoxy, propoxy, isopropoxy or s butoxy.
"Halogen" is Cl, Br, F or I.
The term "pharmaceutically acceptable acid addition salts" embraces
salts with inorganic and organic acids, such as, hydrochloric acid,
hydrobromic acid, nitric acid, surfuric acid, phosphoric acid,
citric acid, formic acid, fumaric acid, maleic acid, acetic acid,
succinic acid, tartaric acid, methanesulfonic acid,
p-toluenesulfonic and the like.
R.sup.7 can conveniently be lower-alkyl, preferably methyl.
Compounds in which R.sup.7 is hydrogen are also preferred. When
R.sup.7 is methyl, compounds in which R.sup.5 and R.sup.6 are
hydrogen are especially preferred.
Furthermore, compounds in which R.sup.1 is hydrogen or methyl,
R.sup.2 is hydrogen or fluorine, R.sup.3 is hydrogen or chlorine
and R.sup.4 is hydrogen are preferred.
Some particularly preferred representatives of the class of
substance defined by formula I in the scope of the invention
are:
2-(5-Fluoroindol-1-yl)-ethylamine;
2-(6-chloro-5-fluoro-indol-1-yl)-ethylamine;
2-(4-methyl-3-methoxy-indol-1-yl)-ethylamine; and
(RS)-2-(6-chloro-5-fluoro-indol-1-yl)-1-methyl-ethylamine.
Examples of other preferred compounds of formula I are:
2-(4-Chloro-5-fluoro-3-methoxy-indol-1-yl)-ethylamine;
2-(5-fluoro-3-methoxy-indol-1-yl)-ethylamine;
2-(5-chloro-indol-1-yl)-ethylamine;
2-(4-chloro-5-fluoro-indol-1-yl)-ethylamine;
(RS)-2-(5-chloro-indol-1-yl)-1-methyl-ethylamine;
(RS)-2-(5-fluoro-indol-1-yl)-1-methyl-ethylamine;
(RS)-2-(6-chloro-5-fluoro-indol-1-yl)-1-methyl-ethyl amine;
(R)-2-(5-fluoro-indol-1-yl)-1-methyl-ethylamine;
(S)-2-(6-chloro-5 -fluoro-indol-1-yl)-1-methyl-ethylamine;
(R)-2-(6-chloro-5-fluoro-indol-1-yl)-1-methyl-ethylamine;
(RS)-2-(4-methyl-indol-1-yl)-1-methyl-ethylamine;
(RS)-2-(5-bromo-indol-1-yl)-1-methyl-ethylamine;
(RS)-2-(6-fluoro-indol-1-yl)-1-methyl-ethylamine;
(S)-2-(5,6-difluoro-indol-1-yl)-1-methyl-ethylamine;
(R)-2-(5,6-difluoro-indol-1-yl)-1-methyl-ethylamine;
(S)-2-(5-fluoro-4-trifluoromethyl-indol-1-yl)-1-methyl-ethylamine;
(S)-2-(5-fluoro-6-trifluoromethyl-indol-1-yl)-1-methyl-ethylamine;
(S)-2-(4-chloro-5-fluoro-indol-1-yl)-1-methyl-ethylamine; and
(R)-2-(4-chloro-5-fluoro-indol-1-yl)-1-methyl-ethylamine.
The compounds of formula I as well as their pharmaceutically
acceptable acid addition salts can be prepared in accordance with
the invention by
a) converting a compound of the formula ##STR6## wherein R.sup.1 to
R.sup.7 have the significances given above and R.sup.81 is a
residue convertible into a amino group, into the corresponding
amino compound, or
b) reacting a compound of the formula ##STR7## wherein R.sup.1 to
R.sup.7 have the significances given above and R.sup.82 is a
leaving group,
with ammonia; and
c) if desired, converting the compound of formula I obtained into a
pharmaceutically acceptable acid addition salt.
The compounds of formula IIa in which R.sup.81 is a residue
convertible into an amino group, preferably an azido group, but
also a nitro group, can be prepared according to known methods.
When R.sup.81 is an azido group, the compounds of formula I are
prepared by reduction. This reduction can be carried out with
complex hydrides, for example, lithium aluminum hydride or by
catalytic hydrogenation on metal catalysts, for example, platinum
or palladium. When lithium aluminum hydride is used as the reducing
agent, anhydrous ether or tetrahydrofuran are suitable as the
solvent. The reduction can be conveniently carried out as follows:
after the dropwise addition of the compound IIa wherein R.sup.81 is
N.sub.3 to a solution consisting of the anhydrous solvent and the
hydride, the mixture is boiled at reflux, subsequently hydrolyzed
with aqueous ether or THF solution and the aluminum hydroxide and
lithium hydroxide precipitate is extracted with THF.
The catalytic hydrogenation on metal catalysts, for example,
platinum or palladium, is effected at room temperature. Especially
suitable solvents are: water, alcohols, such as, methanol, ethenol
and the like, ethyl acetate, dioxane, glacial acetic acid or
mixture of these solvents.
The hydrogenation is effected under a hydrogen atmosphere either in
an autoclave or in a shaking apparatus.
Compounds of formula I can also be prepared when compounds of
formula IIb in which R.sup.82 is a leaving group, for example,
halogen, especially bromine, are reacted with ammonia.
The compounds of formula IIb are conveniently suspended in liquid
ammonia and stirred in an autoclave while heating. After
evaporation of the ammonia, the residue is taken up in a solvent,
preferably dichloromethane, washed and dried.
It has been found that the acid addition salts of these compounds
are especially well suited for pharmaceutical use. Compounds of
formula I in the form of fumaric acid salts are particularly
suitable, although all other acids mentioned in the description
form pharmaceutically acceptable acid addition salts.
The addition of the corresponding acids to the compounds of formula
I is conveniently effected before their ultimate isolation at the
conclusion of the described process variant.
The indole derivatives which are used as starting materials for the
preparation of the compounds of formula IIa and IIb can be
prepared, for example, by known methods according to the following
Reaction Schemes, for example, according to the Fischer indole
synthesis, where arylhydrazones of aldehydes or ketones are
cyclized under the influence of acids or metal hydrides as the
catalyst with the cleavage of ammonia: ##STR8## In this, the
substituents R.sup.1 to R.sup.6 have the above significance.
Corresponding indole derivatives can also be prepared according to
the following Scheme in analogy to processes described in
Synthesis, 1985, p. 186: ##STR9## In this, R.sup.1 to R.sup.4 have
the significances given above and R' is lower-alkyl.
Aromatic aldehydes are converted into alkyl a-azidocinnamates by an
alkoxide-catalyzed condensation with alkyl azidoacetates in a
one-stage reaction and in good yields.
A thermolysis in boiling p-xylene subsequently leads in almost
quantitative yield to alkyl indole-2-carboxylates. The ester group
can be hydrolyzed according to known methods and the acid group can
be cleaved off thermally.
Furthermore, indole compounds can be obtained when a
correspondingly substituted phenylglycine is cyclized, as Scheme 3
hereinafter shows: ##STR10## R.sup.1 to R.sup.4 have the
significances given above and R.sup.8 and R.sup.9 are lower alkyl,
whereby R.sup.8 and R.sup.9 can be the same or different.
The compounds of formula V can be converted into the compounds of
formula VI with alcohols according to known methods. By cyclizing a
compound of formula VI, there is obtained an indole of formula VII
(J. Het. Chem. 16, 221 (1979)). The compounds of formula VIII are
obtained by reacting an indole of formula VII with an alkylating
agent, for example, with a dialkyl sulfate or with diazomethane.
This reaction is effected in alcoholic solvents, preferably
methanol, at room temperature.
Reaction Scheme 4 shows another method for the preparation of
corresponding indoles as starting materials for the preparation of
the compounds of formula I.
In this case also, the preparation starts from a correspondingly
substituted phenyl glycine of formula V. ##STR11## The substituent
designations for R.sup.1 to R.sup.4 correspond to those given
above, R.sup.51 is lower-alkoxy and R is lower-alkyl.
A compound of formula V can be converted with an acetate,
preferably sodium acetate, in acetic anhydride under reflux, into a
compound of formula IX, which can be converted by hydrolysis, for
example, with concentrated surfuric acid, into a compound of
formula X. The compounds of formula X are known (see Proc. Roy.
Soc. London, 178 B, 781 (195 8 ) ) or can be prepared in an
analogous manner.
Alkylation of a compound of formula X can be effected with
conventional alkylating agents, for example, dialkyl sulfates.
Methylation is preferably effected with dimethyl sulfate to a
compound of formula XI analogously to the disclosure appearing in
Bull. Soc. Chem. France 1978, 651.
The cleavage of the N-acetyl group can be effected using
conventional methods, for example by reaction with a sodium
alcoholate in an alcoholic solvent, preferably sodium methylate in
methanol.
Another possibility for the preparation of the compounds of formula
XII comprises hydrolyzing the indole esters of formula XIV to the
acids of formula XIII. Alkali hydroxide is conveniently used for
this purpose.
The decarboxylation of the compounds of formula XIII to the
corresponding compounds of formula XII can be effected by the
action of temperatures between 300.degree. to 320.degree. C. in a
metal bath.
The compounds of formula II are prepared according to Scheme 5
starting from the described indole compounds of formula IV.
##STR12## In Reaction Scheme 5, R.sup.1 to R.sup.6 have the
significances given above.
A compound of formula IIb.sub.1 is obtained by treating a compound
of formula IV with a suitable alkylating agent, preferably
1,2-dibromoethane. This reaction is conveniently carried out under
conditions utilized for phase transfer catalysis. Such a reaction
is effected while stirring in a two-phase system of water and a
water-immiscible organic solvent in the presence of a strong base
and a phase transfer catalyst. 1,2-Dibromoethane, when it
simultaneously serves as the reagent, can conveniently be used as
the organic solvent. A suitable strong base is, for example,
potassium hydroxide or sodium hydroxide. The conventional phase
transfer catalysts can be used. Suitable catalysts are, for
example, benzyltrimethyl-ammonium chloride, tetrabutylammonium
bromide and similar compounds. The reaction is preferably carried
out at a temperature in the range of about 20.degree. to 80.degree.
C.
The compound of formula IIa.sub.1 can be prepared, for example, by
reacting compounds of formula IV with an epoxide.
The compounds of formula IV can preferably be dissolved at about
0.degree. C. in a suspension consisting of sodium hydride and
tetra-hydrofuran and subsequently treated with an alkyloxirane, to
give the corresponding compounds of formula IIa.sub.1.
The hydroxy group can be replaced by a leaving group according to
known methods, for example, by reaction with a sulfonyl chloride,
preferably with methanesulfonyl chloride, to give o the sulfonate.
Compounds of formula IIa.sub.2 or IIb.sub.1 can be converted into
the corresponding azido compounds by treatment with an azide,
preferably sodium azide, in a polar solvent such as, for example,
DMF.
As mentioned earlier, the compounds of formula I and their
pharmaceutically usable acid addition salts possess valuable
pharmacodynamic properties. They have the capacity to bind to
serotonin receptors and are accordingly suitable for the treatment
or prophylaxis of illnesses and disorders of the kind referred to
earlier and, respectively, for the preparation of corresponding
medicaments.
The binding of a compound of formula I to serotom receptors was
determined in vitro by standard methods. The preparations were
investigated in accordance with the tests given hereinafter:
METHOD 1
a) For the binding to the 5HT.sub.1A receptor in accordance with
the .sup.3 H-8-OH-DPAT binding assay according to the method of S.
J. Peroutka, Biol. Psychiatry 20, 971-979 (1985).
b) For the binding to the 5HT.sub.2C receptor in accordance with
the .sup.3 H-mesulergin binding assay according to the method of
A.Pazos et al., Europ. J. Pharmacol. 106, 539-546 or D.Hoyer,
Receptor Research 8, 59-81 (1988).
c) For the binding to the 5HT.sub.2A receptor in accordance with
the .sup.3 H-ketanserine binding assay according to the method of
J. E.Leysen, Molecular Pharmacology 21, 301-304 (198 1 ).
The IC.sub.50 values of the test substances were determined, that
is, the concentration in nmol by which 50% of the receptor-bound
ligands are displaced.
The thus-determined activity of some compounds in accordance with
the invention as well as those of some comparative compounds will
be evident from the following Table:
______________________________________ Test method Substance a b c
______________________________________ Buspirone 19.50 3700.0 990.0
NAN-190 0.56 1800.0 581.0 5HT 1.50 9.5 1730.0 Metergoline 4.80 5.5
64.9 mCPP 227.00 53.0 319.0 RU 24969 8.00 159.0 2500.0 CP93129
1620.00 2780.0 29200.0 Ritanserine 5740.00 37.0 3.1 Pirenperone
2870.00 37.0 12.9 ______________________________________ Test
method Substance Example a b c
______________________________________ A 1 1300 87 1580 B 2 3330 43
573 C 3 5070 533 6330 D 4 309 194 2720 E 5 3680 23,5 320 F 6 3470
32 1310 G 7 2370 64 850 H 8 5650 63 2490 I 9 7220 81 740 J 10 2420
13.5 922 K 11 5070 113 1340 L 12 inact. 75 1430 M 14 3080 9.5 860 N
13 1570 44.5 893 O 15 8650 77 1140 P 16 4060 168 4000 U 24 5590 25
403 Q 18 2430 58 2700 R 20 inact. 47 2120 S 19 5010 94 3260 T 23
9450 14 402 V 25 4740 629 5060
______________________________________
A 2-(5-Fluoro-indol-1-yl)-ethylamine fumarate.
B 2-(4-Chloro-5-fluoro-3-methoxy-indol-1-yl)-ethylamine
fumarate.
C 2-(5-Fluoro-3-methoxy-indol-1-yl)-ethylamine fumarate.
D 2-(5-Chloro-indol-1-yl)-ethylamine fumarate.
E 2-(4-Chloro-5-fluoro-indol-1-yl)-ethylamine fumarate.
F 2-(6-Chloro-5-fluoro-indol-1-yl)-ethylamine fumarate.
G 2-(4-Methyl-3-methoxy-indol-1-yl)-ethylamine fumarate.
H (RS)-2-(5-Chloro-indol-1-yl)-1-methyl-ethylamine fumarate.
I (RS)-2-(5-Fluoro-indol-1-yl)-1-methyl-ethylamine fumarate.
J (RS)-2-(6-Chloro-5-fluoro-indol-1-yl)-1-methyl-ethylamine
fumarate.
K (R)-2-(5-Fluoro-indol-1-yl)-1-methyl-ethylamine fumarate.
L (S)-2-(5-Fluoro-indol-1-yl)-1-methyl-ethylamine fumarate.
M (S)-2-(6-Chloro-5-fluoro-indol-1-yl)-1-methyl-ethylamine
fumarate.
N (R)-2-(6-Chloro-5-fluoro-indol-1-yl)-1-methyl-ethylamine
fumarate.
O (RS)-2-(4-Methyl-indol-1-yl)-1-methyl-ethylamine fumarate.
P (RS)-2-(5-Bromo-indol-1-yl)-1-methyl-ethylamine fumarate.
Q (RS)-2-(6-Fluoro-indol-1-yl)-1-methyl-ethylamine fumarate.
R (S)-2-(5,6-Difluoro-indol-1-yl)-1-methyl-ethylamine fumarate.
S (R)-2-(5,6-Difluoro-indol-1-yl)-1-methyl-ethylaraine
fumarate.
T (S)-2-(4-Chloro-5-fluoro-indol-1-yl)-1-methyl-ethylamine
fumarate.
U (R)-2-(4-Chloro-5-fluoro-indol-1-yl)-1-methyl-ethylamine
fumarate.
V (RS)-2-(5-Methyl-indol-1-yl)-1-methyl-ethylamine fumarate.
METHOD II
a) Displacement tests with [3H]-5-HT(1 nM) as the radioligand on
recombinant human-5HT.sub.1A receptors expressed in 3T3 cells of
mice were carried out in order to determine the affinity of a
compound to the 5HT.sub.1A receptor. Membranes which had been
obtained from 2.times.10.sup.5 cells were used as were various
concentrations of the respective test compound.
b) For the binding to the 5HT.sub.2C receptor, in accordance with
the [3H]-5-HT binding assay according to the method of S. J.
Peroutka et al., Brain Research 584, 191-196 (1992).
c) For the binding to the 5HT.sub.2A receptor, in accordance with
the [3H]-DOB binding assay according to the method of T. Branchek
et al., Molecular Pharmacology 38, 604-609 (1990).
The pki values (pki=-log10 Ki) of the test substances are given.
The ki value is defined by the following formula: ##EQU1## in which
the IC.sub.50 values are those concentrations of test compound in
nM by which 50% of the receptor-bound ligands are displaced. [L] is
the concentration of ligand and the K.sub.D value is the
dissociation constant of the ligand.
The thus-determined activity of some compounds in accordance with
the invention will be evident from the following Table:
______________________________________ Test method Example No. a b
c ______________________________________ 30 5.00 8.40 6.73 31 5.50
7.91 6.61 32 6.16 8.21 6,59 33 5.00 8.46 6.91 34 5.00 8.81 7.49 35
5.00 8.28 6.86 36 5.30 8.52 7.12 37 4.98 8.57 8.50 38 <5 7.70
6.80 ______________________________________
In this Table the respective compounds are:
30 (S)-2-(2-Ethyl-5-fluoroindol-1-yl)-1-methyl-ethylamine
fumarate,
31 (S)-2-(4-isopropyl-5-fluoroindol-1-yl)-1-methyl-ethylamine
fumarate,
32 (S)-2-(6-isopropyl-5-fluoroindol-1-yl)-1-methyl-ethylamine
fumarate,
33 (S)-2-(6-chloro-5-fluoro-3-ethylindol-1-yl)-1-methyl-ethylamine
fumarate,
34 (S)-2-(4-chloro-5-fluoro-3-ethylindol-1-yl)-1-methyl-ethylamine
fumarate,
35 (S)-1-methyl-2-(5-fluoro-3-methylindol-1-yl)-ethylamine
fumarate,
36 (S)-2-(6-chloro-5-fluoro-3-methylindol-1-yl)-1-methyl-ethylamine
fumarate,
37
(S)-2-(5-fluoro-3-methoxy-4-methylindol-1-yl)-1-methyl-ethylamine
fumarate,
38 (S)-2-(3-methoxy-4-methylindol-1-yl)-1-methyl-ethylamine
fumarate.
PENILE ERECTION (RATS)
It has been shown that penile erection is dependent on the
stimulation of the 5HT.sub.2C receptor (see Berendsen &
Broekkamp, Eur. J.Pharmacol, 135, 179184 (1987)).
The number of penile erections was determined within 45 minutes
following administration of the test substance to the animal. The
ED.sub.50 is that dosage which brings about 50% of these
erections.
______________________________________ Example No. ED.sub.50
(mg/kg, s.c.) ______________________________________ 1 0.49 2 0.23
3 2.70 4 3.30 5 0.27 6 0.30
______________________________________
The compounds of formula I and the pharmaceutically acceptable acid
addition salts of the compounds of formula I can be used as
medicaments, for example, in the form of pharmaceutical
preparations. The pharmaceutical preparations can be administered
orally, e.g. in the form of tablets, coated tablets, dragees, hard
and soft gelatin capsules, solutions, emulsions or suspensions. The
administration can, however, also be effected rectally, for
example, in the form of suppositories, parenterally, for example,
in the form of injection solutions, or nasally.
For the preparation of pharmaceutical dosage foes, the compounds of
formula I and the pharmaceutically acceptable acid addition salts
of the compounds of formula I can be processed with pharaceutically
inert, inorganic or organic carriers. Lactose, corn starch or
derivatives thereof, talc, stearic acid or its salts and the like
can be used, for example, carriers for tablets, coated tablets,
dragees and hard gelatin capsules. Suitable carriers for soft
gelatin capsules are, for example, vegetable oil, waxes, fats,
semi-solid and liquid polyols and the like. Depending on the nature
of the active substance no carriers are, however, usually required
in the case of soft gelatine capsules. Suitable carriers for the
preparation of solutions and syrups are, for example, water,
polyols, glycerol, vegetable oils and the like. Suitable carriers
for suppositories are, for example, natural or hardened oils,
waxes, fats, semi-liquid or liquid polyols and the like.
The pharmaceutical preparations can, moreover, contain
preservatives, solubilizers, stabilizers, wetting agents,
emulsifiers, sweeteners, colorants, flavorants, salts for varying
the osmotic pressure, buffers, coating agents or antioxidants. They
can also contain still other therapeutically valuable
substances.
Medicaments containing a compound of formula I or a
pharmaceutically acceptable acid addition salt thereof and a
therapeutically inert carrier are also an object of the invention,
as is a process for preparing them which comprises bringing one or
more compounds of formula I and/or pharmaceutically acceptable acid
addition salts thereof into a galenical form for administration
together with one or more therapeutically inert carriers.
In accordance with the invention, compounds of formula I as well as
their pharmaceutically acceptable acid addition salts are useful in
the treament or prevention of central nervous disorders such as
depressions. The compounds of formula I can also be used for the
treatment of bipolar disorders, anxiety states, sleep and sexual
disorders, psychoses, schizophrenia, migraine and other conditions
associated with cephalic pain or pain of a different kind,
personality disorders or obsessive-compulsive disorders, social
phobias or panic states, mental organic disorders, mental disorders
in childhood, aggressiveness, age-associated memory impairment and
behavioural disorders, addiction, obesity, bulimia and the like;
central nervous system damage caused by trauma, stroke,
neurodegenerative diseases and the like; cardiovascular disorders,
such as, hypertension, thrombosis, stroke and the like; and
gastrointestinal disorders, such as, disfunction of the
gastrointestinal tract motility, and, respectively, for the
preparation of the corresponding medicaments. The dosage can vary
within wide limits and will, of course, be fitted to the individual
requirements in each particular case. In the case of oral
administration, the dosage is in a range of about 0.01 mg per
dosage to about 500 mg per day of a compound of formula I or the
corresponding mount of a pharmaceutically acceptable acid addition
salt thereof, although the upper limit can also be exceeded when
this is shown to be indicated.
The following Examples illustrate the invention in more detail. All
temperatures are given in degrees Celsius.
EXAMPLE 1
A solution of 9.8 g of 5-fluoroindole in 360 ml of
1,2-dibromoethane was treated with 180 ml of 28% NaOH and 0.59 g of
tetrabutylammonium bromide. The mixture was stirred at 50.degree.
for 42 hours. The phases were separated and the aqueous phase was
extracted with toluene. The combined organic phases were washed
with water and dried over sodium sulfate. The solvent was distilled
off and the residue was suspended in 1.9 l of liquid ammonia and
stirred in an autoclave at 80.degree. for 15 hours. After
evaporation of the ammonia the residue was taken up in 500 ml of
dichloromethane and washed with 100 ml of water and 100 ml of
saturated sodium chloride solution. The organic phase was dried
over sodium surfate and the solvent was distilled off. The residue
was chromatographed over 350 g of silica gel with ethyl
acetate-methanol (5:1). There were obtained 8.6 g of a reddish oil
which was dissolved in 970 ml of ether and treated with active
charcoal. After filtration the solution was treated with 5.6 g of
fumaric acid and stirred for 2 days. The crystals were filtered off
and dried. There were obtained 11.1 g (39.5%) of
2-(5-fluoro-indol-1-yl)-ethylamine fumarate (1:1.8) with m.p.
173.degree.-175.degree. (dec.)
EXAMPLE 2
a) A suspension of 2.63 g of
N-[3-chloro-2-(hydroxycarbonyl)-4-fluoro-phenyl]glycine and 2.63 g
of sodium acetate in 25 ml of acetic anhydride was boiled under
reflux for 45 minutes. The solvent was removed in a vacuum and the
residue was treated with 50 ml of water. The crystals were filtered
off, washed with water and dried. There were obtained 2.7 g (94%)
of 3-acetoxy-1-acetyl-4-chloro-5-fluoroindole as yellow crystals
with m.p. 168.degree.-169.degree..
b) 2.65 g of 3-acetoxy-1-acetyl-4-chloro-5-fluoroindole were added
to 20 ml of 90% surfuric acid and the reaction mixture, after
stirring for three quarters of an hour, was diluted with 100 ml of
ice-water. The precipitate was filtered off, washed with water and
dried. There were obtained 2 g (92.5%) of
1-acetyl-4-chloro-5-fluoroindolin-3-one as pale brown crystals with
a m.p. of 203.degree.-204.degree..
c) A mixture of 2 g of 1-acetyl-4-chloro-5-fluoroindolin-3-one, 2 g
of powdered sodium hydroxide and 30 ml of dimethyl sulfate was
stirred at room temperature for 5 hours. After the addition of 250
ml of saturated sodium bicarbonate solution the mixture was stirred
overnight and subsequently filtered. The residue was filtered in
150 ml of ether and 100 ml of ethyl acetate. The solution was dried
over sodium sulfate, filtered and evaporated. There were obtained 2
g (95%) of 1-acetyl-4-chloro-5-fluoro-3-methoxyindole as greenish
crystals with m.p. 114.degree.-115.degree..
d) A solution of 2 g of 1-acetyl-4-chloro-5-fluoro-3-methoxyindole
and 0.48 of sodium methylate in 35 ml of methanol was stirred at
room temperature for one hour. After removal of the solvent the
residue was extracted with water and ethyl acetate and the organic
phase was washed with saturated sodium chloride solution and dried
over sodium sulfate. The solvent was removed and the residue was
chromatographed over 100 g of silica gel with hexane-ethyl acetate
(3:1). 0.88 g (53%) of 4ochloro-5-fluoro-3-methoxyindole was
obtained.
e) A solution of 2 g of 4-chloro-5-fluoro-3-methoxyindole in 50 ml
of 1,2-dibromoethane was treated with 50 ml of 28% NaOH and 100 mg
of tetrabutyl-ammonium bromide. The mixture was stirred is for 15
hours. The phases were separated and the aqueous phase was
extracted with toluene. The combined organic phases were washed
with water and dried over sodium sulfate. The solvent was distilled
off and the residue was suspended in 200 ml of liquid ammonia and
stirred in an autoclave at 80.degree. for 18 hours. After
evaporation of the ammonia the residue was taken up in 50 ml of
dichloromethane and washed with water and saturated sodium chloride
solution. The organic phase was dried over sodium sulfate and the
solvent was distilled off. The residue was dissolved in 200 ml of
ether and treated with 0.7 g of fumaric acid and stirred for 2
days. The crystals were isolated and dried. There were obtained 2 g
(55%) of 2-(4-chloro-5-fluoro-3-methoxy-indol-1-yl)-ethylamine
fumarate (1:1) as beige crystals with m.p.
195.degree.-196.degree..
EXAMPLE 3
a) 2.2 g of 3-acetoxy-1-acetyl-5-fluoroindole were added to 20 ml
of 90% sulfuric acid and, after stirring for three quarters of an
hour, the reaction mixture was diluted with 100 ml of ice-water.
The precipitate was filtered off, washed with water and dried.
There were obtained 1.6 g (83%) of 1-acetyl-5-fluoroindolin-3-one
as beige crystals with a m.p. of 143.degree.-144.degree..
b) A mixture of 1.6 g of 1-acetyl-5-fluoroindolin-3-one, 1.9 g of
powdered sodium hydroxide and 28 ml of dimethyl sulfate was stirred
at room temperature for two hours. After the addition of 240 ml of
saturated sodium bicarbonate solution the mixture was stirred
overnight and subsequently filtered. The residue was taken up in
100 ml of ether and 100 ml of ethyl acetate. The solution was dried
over sodium sulfate, filtered and evaporated. There were obtained
1.47 g (86%) of 1-acetyl-5-fluoro-3-methoxyindole as greenish
crystals with m.p. 124.degree.-125.degree..
c) A solution of 1.25 g of 1-acetyl-5-fluoro-3-methoxyindole and
0.35 g of sodium methylate in 23 ml of methanol was stirred at room
temperature for one hour. After removal of the solvent the residue
was extracted with water and ethyl acetate and the organic phase
was washed with saturated sodium chloride solution and dried over
sodium sulfate. The solvent was removed and the residue was
distilled in a bulb-tube at a bath temperature of 200.degree. and a
pressure of 50 mbar. 0.76 g (76%) of 5-fluoro-3-methoxyindole was
obtained.
d) A solution of 0.76 g of 5-fluoro-3-methoxyindole in 25 ml of
1,2-dibromoethane was treated with 25 ml of 28% NaOH and 40 mg
(0.12 mmol) of tetrabutyl-ammonium bromide. The mixture was stirred
at 50.degree. for 15 hours. The phases were separated and the
aqueous phase was extracted with toluene. The combined organic
phases were washed with water and dried over sodium sulfate. The
solvent was distilled off and the residue was chromatographed over
60 g of aluminium oxide with hexane-ethyl acetate (5:1). There was
obtained a yellow oil which was suspended in 80 ml of liquid
ammonia and stirred in an autoclave at 80.degree. for 18 hours.
After evaporation of the ammonia the residue was taken up in
dichloromethane and washed with water and saturated sodium chloride
solution. The organic phase was dried over sodium surfate and the
solvent was distilled off. The residue was dissolved in 90 ml of
ether and 3 ml of methanol and treated with 0.35 g of fumaric acid
and stirred for 2 days. The crystals were filtered off and dried.
There was obtained 0.56 g (37.5%) of
2-(5-fluoro-3-methoxy-indol-1-yl)-ethylamine fumarate (1:1) as
beige crystals with a m.p. of 167.degree..
EXAMPLE 4
a) A solution of 1 g of 5-chloroindole in 30 ml of
1,2-dibromoethane was treated with 30 ml of 28% NaOH and 80 mg of
tetrabutyl-ammonium bromide. The mixture was stirred at 50.degree.
for 3 hours. The phases were separated and the aqueous phase was
extracted with toluene. The combined organic phases were washed
with water and dried over sodium sulfate. The solvent was distilled
off and the residue was chromatographed over 150 g of silica gel
with hexane-ethyl acetate (5:1). There were obtained 1.17 g (69%)
of 1-(2-bromoethyl)-5-chloroindole as white crystals with a m.p. of
71.degree..
b) A suspension of 0.55 g of 1-(2-bromoethyl)-5-chloroindole in 60
ml of liquid ammonia was stirred in an autoclave at 80.degree. for
18 hours. After evaporation of the ammonia the residue was taken up
in dichloromethane and washed with water and saturated sodium
chloride solution. The organic phase was dried over sodium surfate
and the solvent was distilled off. The residue was dissolved in 60
ml of ether and 3 ml of methanol and treated with 0.25 g of fumaric
acid and stirred for 2 days. The crystals were filtered off and
dried. There was obtained 0.51 g (88%) of
2-(5-chloroindol-1-yl)-ethylamine fumarate (1:0.7) as white
crystals (m.p. 167.degree.).
EXAMPLE 5
a) 400 ml of 50% potassium hydroxide solution were added dropwise
at 2.degree.-4.degree. over a period of 90 min. to a solution of
145 ml (1.02 mol) of 2-methylacetoacetic ester in 11 of ethanol. 2
l of ice-water were added and the mixture was treated rapidly with
a diazonium salt solution which had been prepared as follows: 200
ml of a 25% hydrochloric acid solution were added dropwise while
cooling with an ice bath to a solution of 145.6 g (1 mol) of
3-chloro-4-fluoroaniline in 1 l of ethanol. Subsequently, 137 ml
(1.02 mol) of isopentyl nitrite were added at 4.degree. within 90
min. The orange emulsion, which resulted from the addition of the
diazonium salt solution, was poured into 4 l of water and extracted
once with 4 l of toluene and twice with 2 l of toluene each time.
The combined organic phases were dried over sodium sulfate,
filtered and concentrated to a volume of 1.5 l. After boiling on a
water separator for 30 minutes a solution of 203 g of
p-toluenesulfonic acid monohydrate in 1.5 l of toluene was added
and the mixture was heated on a water separator for a further hour.
After cooling the mixture was extracted with 1.5 l of 1N
hydrochloric acid, 1.5 l of 1N sodium hydroxide solution and 0.4 l
of saturated sodium chloride solution. The aqueous phases were
back-washed with 1.5 l of toluene and the combined organic phases
were dried over sodium sulfate, filtered and evaporated. The
residue was chromatographed over 3 kg of silica gel with toluene.
10.3 g (4.2%) of ethyl 6-chloro-5-fluoroindole-2-carboxylate were
obtained. A sample was recrystallized from toluene and then showed
a m.p. of 190.degree.-191.degree.. A second fraction contained 7 g
(2.9%) of ethyl 4-chloro-5-fluoroindole-2-carboxylate as brown
crystals with a m.p. of 179.degree.-182.degree..
b) A suspension of 6.3 g of ethyl
4-chloro-5-fluoroindole-2-carboxylate in 260 ml of ethanol was
treated with 130 ml of 2N sodium hydroxide solution and stirred for
3 hours. Ethanol was evaporated and the reaction solution was
adjusted to pH 1 with 25% hydrochloric acid. The precipitate was
washed with water and dried. There were obtained 5.3 g (96%) of
crude 4-chloro-5-fluoroindole-2-carboxylic acid which was used in
the next step without further purification.
c) A metal bath was heated to 300.degree.-320.degree.. 4.8 g of
4-chloro-5-fluoroindole-2-carboxylic acid were introduced under
argon and, after three minutes, the metal bath was removed. The
reaction mixture was distilled in a bulb-tube at 0.15 mbar and
75.degree. bath temperature. There were obtained 3.15 g (83%) of
4-chloro-5-fluoroindole as white crystals with m.p.
41.degree.-43.degree..
d) A solution of 130 mg of 4-chloro-5-fluoroindole in 3.7 ml of
1,2-dibromoethane was treated with 3.7 ml of 28% NaOH and 7.7 mg of
tetrabutylammonium bromide. The mixture was stirred at 50.degree.
for 5 hours. The phases were separated and the aqueous phase was s
extracted with toluene. The combined organic phases were washed
with water and dried over sodium sulfate. The solvent was distilled
off and the residue was chromatographed over 15 g of silica gel
with hexane-ethyl acetate (5:1). There was obtained a yellow oil
which was suspended in 30 ml of liquid ammonia and stirred in an
autoclave at 80.degree. for 16 hours. After evaporation of the
ammonia the residue was taken up in dichloromethane and washed with
water and saturated sodium chloride solution. The organic phase was
dried over sodium sulfate and the solvent was distilled off. The
residue was chromatographed over 15 g of silica gel with ethyl
acetate-methanol (5:1). There were obtained 110 mg of a yellow oil
which was dissolved in 16 ml of ether, treated with 60 mg (0.5
mmol) of fumaric acid and stirred for 2 days. The crystals were
filtered off and dried. There were obtained 150 mg (59%) of
2-(4-chloro-5-fluoro-indol-1-yl)-ethylamine fumarate (1:1) with
m.p. 200.degree.-201.degree. (dec.)
EXAMPLE 6
a) A suspension of 21.8 g of ethyl 6-chloro-5-fluoroindole-2as
carboxylate in 450 ml of ethanol was treated with 180 ml of 2N
sodium hydroxide solution and stirred for 21 hours. The solution
was evaporated and the residue was taken up in 450 ml of water and
treated with 60 ml of 25% hydrochloric acid. The precipitate was
washed with water and dried. 18.8 g (97.7%) of
6-chloro-5-fluoroindole-2-carboxylic acid were obtained. A sample
was recrystallized from toluene and then showed a m.p. of
274.degree.-176.degree..
b) A metal bath was heated to 300.degree.-320.degree.. 6.4 g of
6-chloro-5-fluoroindole-2-carboxylic acid were introduced under
argon and, after three minutes, the metal bath was removed. After
cooling the reaction mixture was chromatographed over 25 g of
silica gel with hexane-ethyl acetate (4:1). There were obtained
4.17 g (85%) of 6-chloro-5-fluoroindole as beige crystals. A sample
was triturated with hexane and then showed a m.p. of
96-98.degree..
c) A solution of 0.95 g of 6-chloro-5-fluoroindole in 30 ml of
1,2-dibromoethane was treated with 30 ml of 28% NaOH and 60 mg of
tetrabutylammonium bromide. The mixture was stirred for 8 hours.
The phases were separated and the aqueous phase was extracted with
toluene. The combined organic phases were washed with water and
dried over sodium sulfate. The solvent was distilled off and the
residue was chromatographed over 100 g of silica gel with
hexane-ethyl acetate (6:1). There was obtained a light brown oil
which was suspended in 120 ml of liquid ammonia and stirred in an
autoclave at 80.degree. for 16 hours. After evaporation of the
ammonia the residue was taken up in dichloromethane and washed with
water and saturated sodium chloride solution. The organic phase was
dried over sodium sulfate and the solvent was distilled off. The
residue was dissolved in 120 ml of ether and 6 ml of methanol,
treated with 0.5 g of fumaric acid and stirred overnight. The
crystals were filtered off and dried. There was obtained 1 g (61%)
of 2-(6-chloro-5-fluoro-indol-1-yl)-ethylamine fumarate (1:0.7)
with m.p. 192.degree.-193.degree. (dec.)
EXAMPLE 7
a) A solution of 1.76 g of ethyl
4-methyl-3-methoxyindole-2-carboxylate in 90 ml of ethanol was
treated with 45 ml of 2N sodium hydroxide solution and stirred at
room temperature for 17 hours. The alcohol was evaporated and the
residue was treated with 60 ml o of 2N hydrochloric acid. The
separated crystals were filtered off, washed with water and dried.
There were obtained 1.2 g (78%) of
4-methyl-3-methoxyindole-2-carboxylic acid as brown crystals with
m.p. 136.degree..
b) 1.2 g of 4-methyl-3-methoxyindole-2-carboxylic acid were heated
at 150.degree. until gas no longer evolved. There was obtained 0.94
g (quant.) of crude 4-methyl-3-methoxyindole which was used in the
next step without further purification.
c) A solution of 0.94 g of 4-methyl-3-methoxyindole in 30 ml of
1,2-dibromoethane was treated with 30 ml of 28% NaOH and 400 mg of
tetrabutylammonium bromide. The mixture was stirred at 40.degree.
for 24 hours. The reaction mixture was diluted with 150 ml of
toluene and washed with 50 ml of water and 25 ml of saturated
sodium chloride solution. The aqueous phases were back-extracted
with 75 ml of toluene. The combined organic phases were dried with
sodium sulfate. The solvent was distilled off and the residue was
chromatographed over 70 g of silica gel with hexane-ethyl acetate
(6:1). There was obtained a red oil which was suspended in 20 ml of
liquid anunonia and stirred in an autoclave at 80.degree. for 16
hours. After evaporation of the ammonia the residue was taken up in
dichloromethane and washed with water and saturated sodium chloride
solution. The organic phase was dried over sodium surfate and the
solvent was distilled off. The residue was dissolved in 60 ml of
ether and treated with 0.3 g of fumaric acid and stirred for 18
hours. The separated crystals were filtered off and dried. There
was obtained 0.5 g (28%) of
2-(4-methyl-3-methoxy-indol-1-yl)-ethylamine fumarate (1:0.9) with
m.p. 163.degree.-164.degree..
EXAMPLE 8
a) A suspension of 0.4 g of sodium hydride dispersion in 60 ml of
tetrahydrofuran was treated with 1.74 g of 5-chloroindole at
0.degree. and stirred at this temperature for 1 hour. After the
addition of 1.6 ml of (RS)-methyloxirane the reaction mixture was
stirred at room temperature for 48 hours and subsequently treated
with 11 ml of water. The mixture was diluted with 300 ml of ether,
washed with 140 ml of water and with 70 ml of saturated sodium
chloride solution and the organic phase was dried over sodium
sulfate. After removal of the solvent the residue was
chromatographed over 60 g of silica gel with toluene-ethyl acetate
(19:1). There were obtained 2.1 g (87%) of
(RS)-1-(5-chloro-indol-1-yl)-propan-2-ol as a yellow oil.
b) A solution of 2 g of (RS)-1-(5-chloro-indol-1-yl)-propan-2-ol in
50 ml of dichloromethane was treated with 5.4 ml of triethylamine
and cooled to 0.degree.. 1.5 ml of methanesulfonyl chloride were
added dropwise to this solution and the reaction mixture was
stirred for 1 hour. The mixture was diluted with 480 ml of ether.
The mixture was washed with 120 ml of 1M sodium carbonate solution
and 60 ml of saturated sodium chloride solution and the aqueous
phase was back-extracted with 240 ml of ether. The combined organic
s phases were dried over sodium sulfate and the solvent was
removed. The residue was dissolved in 50 ml of dimethylformamide
and, after the addition of 1.26 g of sodium azide, stirred at
60.degree. for 7 hours. The mixture was diluted with 500 ml of
ether and extracted twice with 240 ml of water each time and once
with 60 ml of saturated sodium chloride solution. The aqueous phase
was back-extracted with 240 ml of ether and the combined organic
phases were dried over sodium sulfate. The solvent was removed and
the residue was chromatographed over 46 g of silica gel with
toluene. There were obtained 2 g (90%) of
(RS)-1-(2-azido-propyl)-5-chloroindole as a colourless oil.
c) A suspension of 0.2 g of platinum oxide in 40 ml of ethanol was
stirred under a hydrogen atmosphere for half an hour and
subsequently treated with a solution of 1.9 g of
(RS)-1-(2-azido-propyl)-5-chloroindole in 40 ml of ethanol. The
reaction mixture was stirred at room temperature for two hours. The
catalyst was filtered off and washed with ethanol. The solution was
evaporated and the residue was dissolved in 160 ml of ether and
treated with 0.94 g of fumaric acid and stirred overnight. The
separated crystals were filtered off and dried. There were obtained
1.85 g (70%) of (RS)-2-(5-chloro-indol-1-yl)-1-methyl-ethylamine
fumarate (1:1.9) as white crystals with m.p.
183.degree.-185.degree. (dec.)
EXAMPLE 9
a) A suspension of 0.55 g of sodium hydride dispersion in 75 ml of
tetrahydrofuran was treated with 2 g of 5-fluoroindole at 0.degree.
and stirred at this temperature for 1 hour. After the addition of
2.1 ml of (RS)-methyloxirane the reaction mixture was stirred at
room temperature for 24 hours and subsequently treated with 5 ml of
water. The mixture was diluted with ether, washed three times with
75 ml of water each time and with 70 ml of saturated sodium
chloride solution and the organic phase was dried over sodium
sulfate. After removal of the solvent the residue was
chromatographed over 60 g of silica gel with toluene-ethyl acetate
(19:1). There were obtained 1.8 g (62%) of
(RS)-1-(5-fluoro-indol-1-yl)-propan-2-ol as a yellow oil.
b) A solution of 1.75 g of (RS)-1-(5-fluoro-indol-1-yl)-propan-2-ol
in 45 ml of dichloromethane was treated with 3.8 ml of
triethylamine and cooled to 0.degree.. 1.4 ml of methanesulfonyl
chloride as were added dropwise to this solution and the reaction
nfixture was stirred for one hour. The mixture was diluted with
ether. The mixture was washed with 1M sodium carbonate solution and
saturated sodium chloride solution and the aqueous phase was
back-extracted with ether. The combined organic phases were dried
over sodium sulfate and the solvent was removed. The residue was
dissolved in 45 ml of dimethylformamide and, after the addition of
1.18 g of sodium azide, stirred at 60.degree. for 6 hours. The
mixture was diluted with ether and extracted with water and with 60
ml of saturated sodium chloride solution. The aqueous phase was
back-extracted with ether and the combined organic phases were
dried over sodium sulfate. The solvent was removed and the residue
was chromatographed over 20 g of silica gel with toluene. There
were obtained 1.8 g (91%) of (RS)-1-(2-azido-propyl)-5-fluoroindole
as a colourless oil.
c) A solution of 1.7 g of (RS)-1-(2-azido-propyl)-5-fluoroindole in
80 ml of ethanol was hydrogenated over 170 mg of Pd-C (5%). The
catalyst was filtered off and washed with ethanol. The solution was
evaporated and the residue was dissolved in 240 ml of ether and
treated with 0.93 g of fumaric acid and stirred overnight. The
separated crystals were filtered off and dried. There were obtained
2.3 g (95.8%) of (RS)-2-(5-fluoro-indol-1-yl)-1-methyl-ethylamine
fumarate (1:1) as white crystals with m.p. 169.degree.-170.degree.
(dec.)
EXAMPLE 10
a) A suspension of 0.75 g of sodium hydride dispersion in 100 ml of
tetrahydrofuran was treated with 3.38 g of 6-chloro-5-fluoroindole
at 0.degree. and stirred at this temperature for 1 hour. After the
addition of 2.8 ml of (RS)-methyloxirane the reaction mixture was
stirred at room temperature for 48 hours and subsequently treated
with 11 ml of water. The mixture was diluted with ether, washed
with water and with saturated sodium chloride solution and the
organic phase was dried over sodium sulfate. After removal of the
solvent the residue was chromatographed over 75 g of silica gel
with toluene-ethyl acetate (19:1). There were obtained 2.87 g (63%)
of (RS)-1-6-chloro-5-fluoro-indol-1-yl)-propan-2-ol as beige
crystals with m.p. 185.degree.-186.degree..
b) A solution of 2.85 g of
(RS)-1(6-chloro-5-fluoro-indol-1-yl)-propan-2-ol in 60 ml of
dichloromethane was treated with 5.2 ml of triethylamine and cooled
to 0% 1.9 ml of methanesulfonyl chloride were added dropwise to
this solution and the reaction mixture was stirred for one hour.
The mixture was diluted with ether. The mixture was washed with 1M
sodium carbonate solution and saturated sodium chloride solution
and the aqueous phase was back-extracted with ether. The combined
organic phases were dried over sodium sulfate and the solvent was
removed. The residue was dissolved in 60 ml of dimethylformamide
and, after the addition of 1.55 g of sodium azide, stirred at
60.degree. for 3 hours. The mixture was diluted with ether and
extracted twice with water and with saturated sodium chloride
solution. The aqueous phase was back-extracted with ether and the
combined organic phases were dried over sodium sulfate. The solvent
was removed and the residue was chromatographed over 60 g of silica
gel with toluene. There were obtained 2.87 g (92%) of
(RS)-1-(2-azido-propyl)-6-chloro-5-fluoroindole as a yellowish
oil.
c) A suspension of 0.26 g of platinum oxide in 50 ml of ethanol was
stirred under a hydrogen atmosphere for half an hour and
subsequently treated with a solution of 2.8 g of
(RS)-1-(2-azido-propyl)-6-chloro-5-fluoroindole in 50 ml of
ethanol. The reaction mixture was stirred at room temperature for
two hours. The catalyst was filtered off and washed with ethanol.
The solution was evaporated and the residue was dissolved in 380 ml
of ether and treated with 1.28 g of fumaric acid and stirred
overnight. The separated crystals were filtered off and dried.
There were obtained 3.6 g (95%) of
(RS)-2o(6-chloro-5-fluoro-indol-1-yl)-1-methyl-ethylamine fumarate
(1:1) as white crystals with m.p. 174.degree.-175.degree.
(dec.)
EXAMPLE 11
a) A suspension of 0.26 g of sodium hydride dispersion in 35 ml of
tetrahydrofuran was treated with 0.95 g of 5-fluoroindole at
0.degree. and stirred at this temperature for 1 hour. After the
addition of 1 ml of (S)-methyloxirane the reaction mixture was
stirred at room temperature for 48 hours and subsequently treated
with 7 ml of water. The mixture was diluted with 180 ml of ether,
washed twice with 90 ml of water each time and with 50 ml of
saturated sodium chloride solution and the organic phase was dried
over sodium sulfate. After removal of the solvent the residue was
chromatographed over 28 g of silica gel with toluene-ethyl acetate
(19:1). There were obtained 1.15 g (84%) of
(S)-1-(5-fluoro-indol-1-yl)-propan-2-ol as a light brown oil.
b) A solution of 1.1 g of (S)-1-(5-fluoro-indol-1-yl)-propan-2-ol
in 30 ml of dichloromethane was treated with 3.17 ml of
triethylamine and cooled to 0.degree.. 0.88 ml of methanesulfonyl
chloride was added dropwise to this solution and the reaction
mixture was stirred for one hour. The mixture was diluted with 280
ml of ether. The mixture was washed twice with 70 ml of 1M sodium
carbonate solution and 35 ml of saturated sodium chloride solution
each time and the aqueous phase was back-extracted with 140 ml of
ether. The combined organic phases were dried over sodium sulfate
and the solvent was removed. The residue was dissolved in 30 ml of
dimethylformamide and, after the addition of 0.74 g of sodium
azide, stirred at 60.degree. for 7 hours. The mixture was diluted
with 280 ml of ether and extracted twice with 140 ml of water each
time and once with 70 ml of saturated sodium chloride solution. The
aqueous phase was back-extracted with 140 ml of ether and the
combined organic phases were dried over sodium sulfate. The solvent
was removed and the residue was chromatographed over 25 g of silica
gel with toluene. There were obtained 1.14 g (95%) of
(R)-1-(2-azido-propyl)-5-fluoroindole as a yellowish oil.
c) A suspension of 0.1 g of platinum oxide in 25 ml of ethanol was
stirred under a hydrogen atmosphere for half an hour and
subsequently treated with a solution of 0.92 g of
(R)-1-(2-azido-propyl)-5-fluoroindole in 25 ml of ethanol. The
reaction mixture was stirred at room temperature for two hours. The
catalyst was filtered off and washed with ethanol. The solution was
evaporated and the residue was dissolved in 150 ml of ether and
treated with 0.58 g (5 mmol) of fumaric acid and stirred overnight.
The separated crystals were filtered off and dried. There were
obtained 1.14 g (88%) of
(R)-2-(5-fluoro-indol-1-yl)-1-methyl-ethylamine fumarate (1:1) as
white crystals with m.p. 159.degree.-161.degree. (dec.)
EXAMPLE 12
a) A suspension of 0.26 g of sodium hydride dispersion in 35 ml of
tetrahydrofuran was treated with 0.95 g (7 mmol) of 5-fluoroindole
at 0.degree. and stirred at this temperature for 1 hour. After the
addition of 1 ml of (R)-methyloxirane the reaction mixture was
stirred at room temperature for 48 hours and subsequently treated
with 7 ml of water. The mixture was diluted with 180 ml of ether,
washed twice with 90 ml of water each time and with 50 ml of
saturated sodium chloride solution and the organic phase was dried
over sodium sulfate. After removal of the solvent the residue was
chromatographed over 28 g of silica gel with toluene-ethyl acetate
(19:1). There were obtained 1.09 g (80%) of
(R)-1-(5-fluoro-indol-1-yl)-propan-2-ol as a light brown oil.
b) A solution of 1.04 g of (R)-1-(5-fluoro-indol-1-yl)-propan-2-ol
in 30 ml of dichloromethane was treated with 3.17 ml of
triethylamine and cooled to 0.degree.. 0.88 ml of methanesulfonyl
chloride was added dropwise to this solution and the reaction
mixture was stirred for one hour. The mixture was diluted with 280
ml of ether. The mixture was washed twice with 70 ml of 1M sodium
carbonate solution and 35 ml of saturated sodium chloride solution
and the aqueous phase was back-extracted with 140 ml of ether. The
combined organic phases were dried over sodium sulfate and the
solvent was removed. The residue was dissolved in 30 ml of
dimethylformamide and, after the addition of 0.74 g of sodium
azide, stirred at 60.degree. for 7 hours. The mixture was diluted
with 280 ml of ether and extracted twice with 140 ml of water and
once with 70 ml of saturated sodium chloride solution. The aqueous
phase was back-extracted with 140 ml of ether and the combined
organic phases were dried over sodium sulfate. The solvent was
removed and the residue was chromatographed over 25 g of silica gel
with toluene. There were obtained 1.14 g (97.4%) of
(S)-1-(2-azido-propyl)-5-fluoroindole as a yellowish oil.
c) A suspension of 0.1 g of platinum oxide in 25 ml of ethanol was
stirred under a hydrogen atmosphere for half an hour and
subsequently treated with a solution of 1.12 g of
(S)-1-(2-azido-propyl)-5-fluoroindole in 25 ml of ethanol. The
reaction mixture was stirred at room temperature for two hours. The
catalyst was filtered off and washed with ethanol. The solution was
evaporated and the residue was dissolved in 150 ml of ether and
treated with 0.58 g of fumaric acid and stirred overnight. The
separated crystals were filtered off and dried. There were obtained
1.42 g (90%) of
S)-2-(6-chloro-5-fluoro-indol-1-yl)-1-methyl-ethylamine fumarate
(1:1) as white crystals with m.p. 159.degree.-161.degree.
(dec.)
EXAMPLE 13
a) A suspension of 0.11 g of sodium hydride dispersion in 15 ml of
tetrahydrofuran was treated with 0.5 g of 6-chloro-5-fluoroindole
at 0.degree. and stirred at this temperature for 1 hour. After the
addition of 0.42 ml of (S)-methyloxirane the reaction mixture was
stirred at room temperature for 85 hours and subsequently treated
with water. The mixture was diluted with ether, washed with water
and with saturated sodium chloride solution and the organic phase
was dried over sodium sulfate. After removal of the solvent the
residue was chromatographed over 25 g of silica gel with
toluene-ethyl acetate (19:1). There was obtained 0.54 g (79%) of
(S)-1-(6-chloro-5-fluoro-indol-1-yl)-propan-2-ol as beige crystals
(m.p. 99.degree.-101.degree.).
b) A solution of 0.53 g of
(S)-1-(6-chloro-5-fluoro-indol-1-yl)-propan-2-ol in 30 ml of
dichloromethane was treated with 1 ml of triethylamine and cooled
to 0.degree.. 0.36 ml of methanesulfonyl chloride was added
dropwise to this solution and the reaction mixture was stirred for
one hour. The mixture was diluted with ether. The mixture was
washed with 1M sodium carbonate solution and saturated sodium
chloride solution and the aqueous phase was back-extracted
extracted with ether. The combined organic phases were dried over
sodium sulfate and the solvent was removed. The residue was
dissolved in 10 ml of dimethylformamide and, after the addition of
0.3 g of sodium azide, stirred at 60.degree. for 7 hours. The
mixture was diluted with ether and extracted with water and with
saturated sodium chloride solution. The aqueous phase was
back-extracted with ether and the combined organic phases were
dried over sodium sulfate. The solvent was removed and the residue
was chromatographed over 20 g of silica gel with toluene-n-hexane
(9:1). There was obtained 0.54 g (92%) of
(R)-1-(2-azido-propyl)-6-chloro-5-fluoroindole as a yellowish
oil.
c) A suspension of 0.05 g of platinum oxide in 10 ml of ethanol was
stirred under a hydrogen atmosphere for half an hour and
subsequently treated with a solution of 0.51 g of
(R)-1-(2-azido-propyl)-6-chloro-5-fluoroindol in 10 ml of ethanol.
The reaction mixture was stirred at room temperature for two hours.
The catalyst was filtered off and washed with ethanol. The solution
was evaporated and the residue was dissolved in 60 ml of ether and
treated with 0.23 g of fumaric acid and stirred overnight. The
separated crystals were filtered off and dried. There was obtained
0.55 g (69%) of
(R)-2-(6-chloro-5-fluoro-indol-1-yl)-1-methyl-ethylamine fumarate
(1:1.5) as white crystals with m.p. 153.degree.-154.degree.
(dec.)
EXAMPLE 14
a) A suspension of 0.11 g of sodium hydride dispersion in 15 ml of
tetrahydrofuran was treated with 0.5 g of 6-chloro-5-fluoroindole
at 0.degree. and stirred at this temperature for 1 hour. After the
addition of 0.42 ml of (R)-methyloxirane the reaction mixture was
stirred at room temperature for 85 hours and subsequently treated
with is water. The mixture was diluted with ether, washed with
water and with saturated sodium chloride solution and the organic
phase was dried over sodium sulfate. After removal of the solvent
the residue was chromatographed over 25 g of silica gel with
toluene/ethyl acetate (19:1). There was obtained 0.51 g (74.6%) of
(R)-1-(6-chloro-5-fluoro-indol-1-yl)-propan-2-ol as white crystals
(m.p. 104.degree.-105.degree..)
b) A solution of 0.28 g of
(R)-1-(6-chloro-5-fluoro-indol-1-yl)-propan-2-ol in 6 ml of
dichloromethane was treated with 0.5 ml of triethylamine and cooled
to 0.degree.. 0.2 ml of methanesulfonyl chloride was added dropwise
to this solution and the reaction mixture was stirred for 1 hour.
The mixture was diluted with ether. The mixture was washed with 1M
sodium carbonate solution and saturated sodium chloride solution
and the aqueous phase was back-extracted with ether. The combined
organic phases were dried over sodium sulfate and the solvent was
removed. The residue was dissolved in 6 ml of dimethylformamide
and, after the addition of 0.16 g of sodium azide, stirred at
60.degree. for 7 hours. The mixture was diluted with ether and
extracted with water and with saturated sodium chloride solution.
The aqueous phase was back-extracted with ether and the combined
organic phases were dried over sodium sulfate. The solvent was
removed and the residue was chromatographed over 10 g of silica gel
with toluene. There was obtained 0.29 g (93.5%) of
(S)-1-(2-azido-propyl)-6-chloro-5-fluoroindole as a yellowish
oil.
c) A suspension of 0.02 g of platinum oxide in 5 ml of ethanol was
stirred under a hydrogen atmosphere for half an hour and
subsequently treated with a solution of 0.26 g of
(S)-1-(2-azido-propyl)-6-chloro-5-fluoroindole in 5 ml of ethanol.
The reaction mixture was stirred at room temperature for two hours.
The catalyst was filtered off and washed with ethanol. The solution
was evaporated and the residue was dissolved in 30 ml of ether and
treated with 0.12 g of fumaric acid and stirred overnight. The
separated crystals were filtered off and dried. There was obtained
0.25 g (58.8%) of
(S)-2-(6-chloro-5-fluoro-indol-1-yl)-1-methyl-ethylamine fumarate
(1:1.6) as white crystals with m.p. 151.degree.-152.degree.
(dec.)
EXAMPLE 15
a) A suspension of 0.26 g of sodium hydride dispersion in 35 ml of
tetrahydrofuran was treated with 0.95 g of 4-methylindole at
0.degree. as and stirred at this temperature for 1 hour. After the
addition of 1 ml of (RS)-methyloxirane the reaction mixture was
stirred at room temperature for 48 hours and subsequently treated
with water. The mixture was diluted with ether, washed with water
and with saturated sodium chloride solution and the organic phase
was dried over sodium sulfate. After removal of the solvent the
residue was chromatographed over 25 g of silica gel with
toluene-ethyl acetate (19:1). There was obtained 0.86 g (62.7%) of
(RS)-1-(4-methyl-indol-1-yl)-propan-2-ol as a yellow oil.
b) A solution of 0.74 g of (RS)-1-(4-methyl-indol-1-yl)-propan-2-ol
in 20 ml of dichloromethane was treated with 1.6 ml of
triethylamine and cooled to 0.degree.. 0.6 ml of methanesulfonyl
chloride was added dropwise to this solution and the reaction
mixture was stirred for 1 hour. The mixture was diluted with ether.
The mixture was washed with 1M sodium carbonate solution and
saturated sodium chloride solution and the aqueous phase was
back-extracted with ether. The combined organic phases were dried
over sodium sulfate and the solvent was removed. The residue was
dissolved in 20 ml of dirnethylformamide and, after the addition of
0.5 g of sodium azide, stirred at 60.degree. for 7 hours. The
mixture was diluted with ether and extracted with water and
saturated sodium chloride solution. The aqueous phase was
back-extracted with ether and the combined organic phases were
dried over sodium sulfate. The solvent was removed and the residue
was chromatographed over 30 g of silica gel with toluene. There was
obtained 0.68 g (81.2%) of (S)-1-(2-azido-propyl)-4-methylindole as
an orange oil.
c) A solution of 0.67 g of (RS)-1-(2-azido-propyl)-4-methylindole
in 30 ml of ethanol was hydrogenated over 70 mg of Pd-C (5%). The
catalyst was filtered off and washed with ethanol. The solution was
evaporated and the residue was dissolved in 90 ml of ether and
treated with 0.35 g of fumaric acid and stirred overnight. The
separated crystals were filtered off and dried. There was obtained
0.88 g (92.3%) of (RS)-2-(4-methyl-indol-1-yl)-1-methyl-ethylamine
fumarate (1:1) as white crystals with m.p. 163.degree.-164.degree.
(dec.)
EXAMPLE 16
a) A suspension of 0.56 g of sodium hydride dispersion in 75 ml of
tetrahydrofuran was treated with 2.95 g of 5-bromoindole at
0.degree. C. and stirred at this temperature for 1 hour. After the
addition of 2.1 ml of (RS)-methyloxirane the reaction mixture was
stirred at room temperature for 60 hours and subsequently treated
with 15 ml of water. The mixture was diluted with 750 ml of ether,
washed twice with 250 ml of water and with 125 ml of saturated
sodium chloride solution and the organic phase was dried over
sodium sulfate. After removal of the solvent the residue was
chromatographed over 120 g of silica gel with toluene-ethyl acetate
(19:1). There were obtained 3.4 g (89%) of
(RS)-1-(5-bromo-indol-1-yl)-propan-2-ol as a yellow oil.
b) A solution of 3.36 g of (RS)-1-(5-bromo-indol-1-yl)-propan-2-ol
in 60 ml of dichloromethane was treated with 7.37 ml of
triethylamine and cooled to 0.degree.. 2 ml of methanesulfonyl
chloride were added dropwise to this solution and the reaction
mixture was stirred for one hour. The mixture was diluted with 660
ml of ether. The mixture was washed twice with 135 ml of 1M sodium
carbonate solution and 80 ml of saturated sodium chloride solution
and the aqueous phase was back-extracted with 300 ml of ether. The
combined organic phases were dried over sodium sulfate and the
solvent was removed. The residue was dissolved in 60 ml of
dimethylformamide and, after the addition of 1.72 g of sodium
azide, stirred at 60.degree. for 16 hours. The mixture was diluted
with 660 ml of ether and extracted twice with 330 ml of water and
once with 80 ml of saturated sodium chloride solution. The aqueous
phase was back-extracted with 330 ml of ether and the combined
organic phases were dried over sodium sulfate. The solvent was
removed and the residue was chromatographed over 90 g of silica gel
with toluene. There were obtained 3.22 g (87.2%) of
(RS)-1-(2-azido-propyl)-5-bromoindole as a light yellow oil.
c) A suspension of 0.1 g of platinum oxide in 20 ml of ethanol was
stirred under a hydrogen atmosphere for half an hour and
subsequently treated with a solution of 1.12 g of
(RS)-1-(2-azido-propyl)-5-bromoindole in 20 ml of ethanol and 2 ml
of a 33% methylamine solution in ethanol. The reaction mixture was
stirred at room temperature for 4 hours. The catalyst was filtered
off and washed with ethanol. The solution was evaporated and the
residue was dissolved in 120 ml of ether and 2.5 ml of methanol and
treated with 0.46 g of fumaric acid and stirred overnight. The
separated crystals were filtered off and dried. There were obtained
1.38 g (93%) of (RS)-2-(5-bromo-indol-1-yl)-1-methyl-ethylamine
fumarate (1:1) as white crystals with m.p. 192.degree.-193.degree.
(dec.)
EXAMPLE 17
A suspension of 0.28 g of sodium hydride dispersion in 40 ml of
tetrahydrofuran was treated with 0.98 g of 6-methylindole at
0.degree. and stirred at this temperature for 1 hour. After the
addition of 1 ml of (RS)-methyloxirane the reaction mixture was
stirred at room temperature for 60 hours and subsequently treated
with 7 ml of water. The mixture was diluted with 370 ml of ether,
washed twice with 120 ml of water and with 60 ml of saturated
sodium chloride solution and the organic phase was dried over
sodium sulfate. After removal of the solvent the residue was
chromatographed over 35 g of silica gel with toluene-ethyl acetate
(19:1). There was obtained 0.5 g (35%) of
(RS)-1-(6-methyl-indol-1-yl)-propan-2-ol as light brown crystals
with m.p. 65.degree.-69.degree..
b) A solution of 0.49 g of (RS)-1-(6-methyl-indol-1-yl)-propan-2-ol
in 10 ml of dichloromethane was treated with 1 ml of triethylamine
and cooled to 0.degree.. 0.5 ml of methanesulfonyl chloride was
added dropwise to this solution and the reaction mixture was
stirred for one hour. The mixture was diluted with ether. The
mixture was washed twice with 1M sodium carbonate solution and
saturated sodium chloride solution and the aqueous phase was
back-extracted with ether. The combined organic phases were dried
over sodium sulfate and the solvent was removed. The residue was
dissolved in 20 ml of dimethylformamide and, after the addition of
0.5 g of sodium azide, stirred at 60.degree. for 16 hours. The
mixture was diluted with 660 ml of ether and extracted twice with
water and once with 80 ml of saturated sodium chloride solution.
The aqueous phase was back-extracted with ether and the combined
organic phases were dried over sodium sulfate. The solvent was
removed and the residue was chromatographed over 30 g of silica gel
with toluene. There was obtained 0.5 g (90%) of
(RS)-1-(2-azido-propyl)-5-methylindole as a light yellow oil.
c) A solution of 0.5 g of (RS)-I-(2-azido-propyl)-5-methylindole in
20 ml of ethanol was hydrogenated over 70 mg of Pd-C (5%). The
catalyst was filtered off and washed with ethanol. The solution was
evaporated and the residue was dissolved in 100 ml of ether and
treated with 0.25 g of fumaric acid and stirred overnight. The
separated crystals were filtered off and dried. There was obtained
0.43 g (60.5%) of (RS)-2-(6-methyl-indol-1-yl)-1-methyl-ethylamine
fumarate as white crystals with m.p. 152.degree.-153.degree.
(dec.)
EXAMPLE 18
a) A suspension of 0.26 g of sodium hydride dispersion in 35 ml of
tetrahydrofuran was treated with 0.97 g of 6-fluoroindole at
0.degree. and stirred at this temperature for 1 hour. After the
addition of 1 ml of (RS)-methyloxirane the reaction mixture was
stirred at room temperature for 48 hours and subsequently treated
with 7 ml of water. The mixture was diluted with 180 ml of ether,
washed twice with 90 ml of water and with 50 ml of saturated sodium
chloride solution and the organic phase was dried over sodium
sulfate. After removal of the solvent the residue was
chromatographed over 28 g of silica gel with toluene-ethyl acetate
(19:1). There were obtained 1.1 g (79.3%) of
(RS)-1-(6-fluoro-indol-1-yl)-propan-2-ol as a colourless oil.
b) A solution of 1.1 g of (RS)-1-(6-fluoro-indol-1-yl)-propan-2-ol
in 30 ml of dichloromethane was treated with 3.17 ml of
triethylamine and cooled to 0.degree.. 0.88 ml of methanesulfonyl
chloride was added dropwise to this solution and the reaction
mixture was stirred for 1 hour. The mixture was diluted with 280 ml
of ether. The mixture was washed twice with 70 ml of 1M sodium
carbonate solution and 35 ml of saturated sodium chloride solution
and the aqueous phase was back-extracted with 140 ml of ether. The
combined organic phases were dried over sodium sulfate and the
solvent was removed. The residue was dissolved in 20 ml of
dimethylformamide and, after the addition of 0.5 g of sodium azide,
stirred at 60.degree. for 7 hours. The mixture was diluted with 280
ml of ether and extracted twice with 140 ml of water and once with
70 ml of saturated sodium chloride solution. The aqueous phase was
back-extracted with 140 ml of ether and the combined organic phases
were dried over sodium sulfate. The solvent was removed and the
residue was chromatographed over 25 g of silica gel with toluene.
There was obtained 1 g (80.5%) of
(RS)-1-(2-azido-propyl)-6-fluoroindole as a yellowish oil.
c) A solution of I g of (RS)-1-(2-azido-propyl)-6-fluoroindole in
30 ml of ethanol was hydrogenated over 100 mg of Pd-C (5%). The
catalyst was filtered off and washed with ethanol. The solution was
evaporated and the residue was dissolved in 100 ml of ether and
treated with 0.5 g of fumaric acid and stirred overnight. The
separated crystals were isolated and dried. There were obtained 1.1
g (78%) of (RS)-2-(6-fluoro-indol-1-yl)-1-methyl-ethylamine
fumarate (1:1) as white crystals with m.p. 158.degree.-159.degree.
(dec.)
EXAMPLE 19
a) 40 ml of 50% potassium hydroxide solution were added dropwise to
a solution of 14.5 ml of 2-methylacetoacetic ester in 100 ml of
ethanol at 2.degree.-4.degree.. 200 ml of ice-water were added and
the mixture was treated with a diazonium salt solution which had
been prepared as follows: 20 ml of a 25% hydrochloric acid solution
were added dropwise while cooling with an ice bath to a solution of
10 ml of 3,4-difluoroaniline in 100 ml of ethanol. Subsequently,
13.7 ml of isopentyl nitrite were added at 4.degree.. The emulsion
which resulted from the addition of the diazonium salt solution was
poured into water and extracted with toluene. The organic phase was
dried over sodium sulfate, filtered and concentrated to a volume of
160 ml. A solution of 19 g of p-toluenesulfonic acid monohydrate
was, after boiling on a water separator for 1 hour, added and the
mixture was heated for a further hour. After cooling the mixture
was extracted with 1N hydrochloric acid, 1N sodium hydroxide
solution and saturated sodium chloride solution. The aqueous phases
were backwashed with toluene and the combined organic phases were
dried over sodium sulfate, filtered and evaporated. The residue was
chromatographed over 170 g of silica gel with hexane-ethyl acetate
(2:1). 8.9 g (39%) of crude ethyl 4,5-difluoroindole-2-carboxylate
were obtained. A sample was recrystallized from hexane-ethyl
acetate and then showed a m.p. of 149.degree.-150.degree..
b) A solution of 2.06 g of ethyl 5,6-difluoroindole-2-carboxylate
in 90 ml of ethanol was treated with 45 ml of 2N sodium hydroxide
solution and stirred at room temperature for 17 hours. The alcohol
was evaporated and the residue was treated with 50 ml of 2N
hydrochloric acid. The separated crystals were filtered off, washed
with water and dried. 1.78 g (98.8%) of
5,6-difluoroindole-2-carboxylic acid were obtained as brown
crystals with m.p. 279.degree.-280.degree..
c) A metal bath was heated to 330.degree.. 1.74 g of
5,6-difluoroindole-2-carboxylic acid were introduced under argon.
The black reaction residue was chromatographed over 60 g of silica
gel with hexane-ethyl acetate (4:1). 1.11 g (82%) of
5,6-difluoroindole were obtained as pale brown crystals. A sample
was sublimed and then showed a m.p. of 89.degree.-91.degree..
d) A suspension of 0.12 g of sodium hydride dispersion in 15 ml of
tetrahydrofuran was treated with 0.5 g of 5,6-difluoroindole at
0.degree. and stirred at this temperature for 1 hour. After the
addition of 0.46 ml of (R)-methyloxirane the reaction mixture was
stirred at room temperature for 60 hours and subsequently treated
with water. The mixture was diluted with ether, washed twice with
water and with saturated sodium chloride solution and the organic
phase was dried over sodium sulfate. After removal of the solvent
the residue was chromatographed over 35 g of silica gel with
toluene-ethyl acetate (19:1). 0.46 g (66.5%) of
(R)-1-(5,6-difluoro-indol-1-yl)-propan-2-ol was obtained as
yellowish crystals with m.p. 114.degree.-116.degree..
e) A solution of 0.43 g of
(R)-1-(5,6-difluoro-indol-1-yl)-propan-2-ol in 10 ml of
dichloromethane was treated with 0.86 ml of triethylamine and
cooled to 0.degree.. 0.32 ml of methanesulfonyl chloride was added
dropwise to this solution and the reaction mixture was stirred for
1 hour. The mixture was diluted with ether. The mixture was washed
with 1M sodium carbonate solution and saturated sodium chloride
solution and the aqueous phase was back-extracted with ether. The
combined organic phases were dried over sodium sulfate and the
solvent was removed. The residue was dissolved in 10 ml of
dimethylformamide and, after the addition of 0.26 g of sodium
azide, stirred at 60.degree. for 7 hours. The mixture was diluted
with ether and extracted twice with water and once with saturated
sodium chloride solution. The aqueous phase was back-extracted with
ether and the combined organic phases were dried over sodium
sulfate. The solvent was removed and the residue was
chromatographed over 15 g of silica gel with toluene. 0.4 g (83%)
of (S)-1-(2-azido-propyl)-5,6-difluoroindole was obtained as a
yellowish oil.
f) A solution of 0.37 g of
(S)-1-(2-azido-propyl)-5,6-difluoroindole in 15 ml of ethanol was
hydrogenated over 40 mg of Pd-C (5%). The catalyst was filtered off
and washed with ethanol. The solution was evaporated and the
residue was dissolved in 50 ml of ether and treated with 0.17 g of
fumaric acid and stirred overnight. The separated crystals were
isolated and dried. 0.43 g (84%) of
(S)-2-(5,6-difluoro-indol-1-yl)-1-methyl-ethylamine fumarate (1:1)
was obtained as white crystals with m.p. 159.degree.-160.degree.
(dec.)
EXAMPLE 20
a) A suspension of 0.12 g of sodium hydride dispersion in 15 ml of
tetrahydrofuran was treated with 0.5 g of 5,6-difluoroindole at
0.degree. and stirred at this temperature for 1 hour. After the
addition of 0.46 mlof (S)-methyloxirane the reaction mixture was
stirred at room temperature for 60 hours and subsequently treated
with water. The mixture was diluted with ether, washed twice with
water and with saturated sodium chloride solution and the organic
phase was dried over sodium sulfate. After removal of the solvent
the residue was chromatographed over 35 g of silica gel with
toluene-ethyl acetate (19:1). There was obtained 0.5 g (74%) of
(S)-1-(5,6-difluoro-indol-1-yl)-propan-2-ol as yellowish crystals
with m.p. 116.degree.-118.degree..
b) A solution of 0.48 g of
(S)-1-(5,6-difluoro-indol-1-yl)-propan-2-ol in 10 ml of
dichloromethane was treated with 0.97 ml of s triethylamine and
cooled to 0.degree.. 0.36 ml of methanesulfonyl chloride was added
dropwise to this solution and the reaction mixture was stirred for
1 hour. The mixture was diluted with ether. The mixture was washed
twice with 1M sodium carbonate solution and saturated sodium
chloride solution and the aqueous phase was back-extracted with
ether. The combined organic phases were dried over sodium sulfate
and the solvent was removed. The residue was dissolved in 10 ml of
dimethylformamide and, after the addition of 0.29 g of sodium
azide, stirred at 60.degree. for 7 hours. The mixture was diluted
with ether and extracted twice with water and once with saturated
sodium chloride solution. The aqueous phase was back-extracted with
ether and the combined organic phases were dried over sodium
sulfate. The solvent was removed and the residue was
chromatographed over 15 g of silica gel with toluene. There was
obtained 0.48 g (89.4%) of (R)-
I-(2-azido-propyl)-5,6-difluoroindole as a yellowish oil.
c) A solution of 0.45 g of (R)-1-(2-azido-propyl)-5,6difluoroindole
in 20 ml of ethanol was hydrogenated over 40 mg of Pd-C (5%). The
catalyst was filtered off and washed with ethanol. The solution was
evaporated and the residue was dissolved in 50 ml of ether and
treated with 0.21 g of fumaric acid and stirred overnight. The
separated crystals were filtered off and dried. There was obtained
0.51 g (82%) of (R)-2-(S,6-difluoro-indol-1-yl)-1-methyl-ethylamine
fumarate (1:1) as white crystals with m.p. 161.degree.-162.degree.
(dec.)
EXAMPLE 21
a) 56 ml of 50% potassium hydroxide were added dropwise at
2.degree.-4.degree. to a solution of 20.3 ml of 2-methylacetoacetic
ester in 140 ml of a s ethanol. 280 ml of ice-water were added and
the mixture was treated rapidly with a diazonium salt solution
which had been prepared as follows: 28 ml of a 25% hydrochloric
acid solution were added dropwise while cooling with an ice bath to
a solution of 25 g (140 mmol) of 4-fluoro-3-trifluoromethylaniline
in 140 ml of ethanol. Subsequently, 19.2 ml of isopentyl nitrite
were added at 4.degree.. The emulsion which resulted from the
addition of the diazonium salt solution was poured into water and
extracted with toluene. The organic phase was dried over sodium
sulfate, filtered and concentrated to a volume of 250 ml. After
boiling on a water separator for 30 mins. a solution of 26.6 g of
p-toluenesulfonic acid monohydrate in 250 ml of toluene was added
and the mixture was heated for a further hour. After cooling the
mixture was extracted with 1N hydrochloric acid, 1N sodium
hydroxide solution and saturated sodium chloride solution. The
aqueous phases were back-washed with toluene and the combined
organic phases were dried over sodium surfate, filtered and
evaporated. The residue was chromatographed over 200 g of silica
gel with toluene. 3.2 g (6.3%) of crude ethyl
5-fluoro-6-trifluoromethylindole-2-carboxylate were obtained. A
sample was triturated with hexane and then showed a m.p. of
159.degree.-162.degree.. A second fraction contained 1.4 g (3.6%)
of ethyl 5-fluoro-4-trifluoromethylindole-2-carboxylate as orange
crystals with a m.p. of 121.degree.-124.degree..
b) A solution of 2.24 g of ethyl
5-fluoro-4-trifluoromethylindole-2-carboxylate in 80 ml of ethanol
was treated with 40 ml of 2N sodium hydroxide solution and stirred
at room temperature for 1 hour. The alcohol was evaporated and the
solution was adjusted to pH 1 with 2N hydrochloric acid. The
separated crystals were isolated, washed with water and dried.
There were obtained 1.17 g (85%) of
5-fluoro-4-trifluoromethylindole-2-carboxylic acid as beige
crystals with m.p. 204.degree.-210.degree..
c) A suspension of 0.8 g of
5-fluoro-4-trifluoromethylindole-2-carboxylic acid in 16 ml of
diphenyl ether was stirred at 260.degree. for 4 hours and, after
cooling to 0.degree., diluted with 16 ml of tetrahydrofuran. 122 mg
of sodium hydride dispersion were added and the mixture was stirred
for 1 hour. Subsequently, 0.46 ml of (S)-methyloxirane was added
and the reaction mixture was stirred at room temperature for 60
hours. The mixture was extracted with diethyl ether, water and
saturated sodium chloride solution and the organic phase was dried
over sodium sulfate. The solvent was removed and the residue was
chromatographed over 40 g of silica gel with hexane-toluene (1:1)
and subsequently with toluene-ethyl acetate (15:1). There was
obtained 0.3 g (35.5%) of
(R)-1-(5-fluoro-4-trifluoromethyl-indol-1-yl)-propan-2-ol as light
brown crystals.
d) A solution of 0.27 g of
(R)-1-(5-fluoro-4-trifluoromethyl-indol-1-yl)-propan-2-ol in 5 ml
of dichloromethane was treated with 0.44 ml of triethylamine and
cooled to 0.degree.. 0.16 ml of methanesulfonyl chloride was added
dropwise to this solution and the reaction mixture was stirred for
one hour. The mixture was diluted with ether. The mixture was
washed twice with 1M sodium carbonate solution and saturated sodium
chloride solution and the aqueous phase was back-extracted with
ether. The combined organic phases were dried over sodium sulfate
and the solvent was removed. The residue was dissolved in 5 ml of
dimethylformamide and, after the addition of 0.13 g of sodium
azide, stirred at 60.degree. for 7 hours The mixture was diluted
with ether and extracted twice with water and once with saturated
sodium chloride solution. The aqueous phase was back-extracted with
ether and the combined organic phases were dried over sodium
sulfate. The solvent was removed and the residue was
chromatographed over 10 g of silica gel with toluene-hexane (1:1 ).
There was obtained 0.26 g (87.8%) of
(S)-1-(2-azido-propyl)-5-fluoro-4-trifluoromethylindole as a
colourless oil.
e) A suspension of 26 mg of platinum oxide in 4.5 ml of ethanol was
stirred under a hydrogen atmosphere for half an hour and
subsequently treated with a solution of 0.26 g of
(S)-1-(2-azido-propyl)-5-fluoro-4-trifluoromethylindole in 4.5 ml
of ethanol. The reaction mixture was stirred at room temperature
for 1 hour. The catalyst was filtered off and washed with ethanol.
The solution was evaporated and the residue was dissolved in 27 ml
of ether and 0.3 ml of methanol and treated with 105 mg of fumaric
acid and stirred overnight. The separated crystals were isolated
and dried. There was obtained 0.32 g (93.6%) of
(S)-2-(5-fluoro-4-trifluoro-methylindol-1-yl)-1-methyl-ethylamine
fumarate (1:1) as white crystals with m.p. 180.degree.-181.degree.
(dec.)
EXAMPLE 22
a) A solution of 1.85 g of ethyl
5-fluoro-6-trifluoromethylindole-2-carboxylate in 60 ml of ethanol
was treated with 30 ml of 2N sodium hydroxide solution and stirred
at room temperature for 1 hour. The alcohol was evaporated and the
solution was adjusted to pH 1 with 2N hydrochloric acid. The
separated crystals were isolated, washed with water and dried.
There were obtained 1.5 g (90%) of
5-fluoro-6-trifluoromethylindole-2-carboxylic acid as brown
crystals with m.p. 178.degree.-180.degree..
b) A suspension of 0.75 g of
5-fluoro-6-trifluoromethylindole-2-carboxylic acid in 16 ml of
diphenyl ether was stirred at 260.degree. for 4 hours and, after
cooling to 0.degree., diluted with 16 ml of tetrahydrofuran. 113 mg
of sodium hydride dispersion were added and the mixture was stirred
for 1 hour. Subsequently, 0.43 ml of (R)-methyloxirane was added
and the reaction mixture was stirred at room temperature for 60
hours. The mixture was extracted with diethyl ether, water and
saturated sodium chloride solution and the organic phase was dried
over sodium sulfate. The solvent was removed and the residue was
chromatographed over 40 g of silica gel with hexane-toluene (1:1)
and subsequently with toluene-ethyl acetate (15:1). There was
obtained 0.15 g (18.9%) of
(R)-1-(5-fluoro-6-trifluoromethyl-indol-1-yl)-propan-2-ol as light
brown crystals.
c) A solution of 0.15 g of
(R)-1-(5-fluoro-6-trifluoromethyl-indol-1-yl)-propan-2-ol in 3 ml
of dichloromethane was treated with 0.24 ml of triethylamine and
cooled to 0.degree.. 0.09 ml of methanesulfonyl chloride was added
dropwise to this solution and the reaction mixture was stirred for
1 hour. The mixture was diluted with ether. The mixture was washed
with 1M sodium carbonate solution and saturated sodium chloride
solution and the aqueous phase was back-extracted with ether. The
combined organic phases were dried over sodium sulfate and the
solvent was removed. The residue was dissolved in 3 ml of
dimethylformamide and, after the addition of 0.07 g of sodium
azide, stirred at 60.degree. for 7 hours. The mixture was diluted
with ether and extracted twice with water and once with saturated
sodium chloride solution. The aqueous phase was back-extracted with
ether and the combined organic phases were dried over sodium
sulfate. The solvent was removed and the residue was
chromatographed over 8 g of silica gel with toluene-hexane (1:1).
There was obtained 0.13 g (79.2%) of
(S)-1-(2-azido-propyl)-5-fluoro-6-trifluoromethylindole as a
colourless oil.
d) A suspension of 13 mg of platinum oxide in 2.5 ml of ethanol was
stirred under a hydrogen atmosphere for half an hour and
subsequently treated with a solution of 0.13 g of
(S)-1-(2-azido-propyl)-5-fluoro-6-trifluoromethylindole in 2.5 ml
of ethanol. The reaction mixture was stirred at room temperature
for 1 hour. The catalyst was filtered off and washed with ethanol.
The solution was evaporated and the residue was dissolved in 14 ml
of ether and 0.1 ml of methanol and treated with 53 mg of fumaric
acid and stirred overnight. The separated crystals were filtered
off and dried. There was obtained 0.16 g (93.5%) of
(S)-2-(5-fluoro-6-tri-fluoromethylindol-1-yl)-1-methyl-ethylamine
fumarate (1:1) as white crystals with m.p. 170.degree.-171.degree.
(dec.)
EXAMPLE 23
a) A suspension of 0.11 g of sodium hydride dispersion in 15 ml of
tetrahydrofuran was treated with 0.5 g of 4-chloro-5-fluoroindole
at 0.degree. and stirred at this temperature for 1 hour. After the
addition of 0.4 ml of (R)-methyloxirane the reaction mixture was
stirred at room temperature for 48 hours and subsequently treated
with water. The mixture was diluted with ether, washed with water
and with saturated sodium chloride solution and the organic phase
was dried over sodium sulfate. After removal of the solvent the
residue was chromatographed over 30 g of silica gel with
toluene-ethyl acetate (33:1). There was obtained 0.5 g (74.5%) of
(R)-1-(4-chloro-5-fluoro-indol-1-yl)-propan-2-ol as a yellow
oil.
b) A solution of 0.49 g of
(R)-1-(4-chloro-5-fluoro-indol-1-yl)-propan-2-ol in 11 ml of
dichloromethane was treated with 0.9 ml of triethylamine and cooled
to 0.degree.. 0.33 ml of methanesulfonyl chloride was added
dropwise to this solution and the reaction mixture was stirred for
one hour. The mixture was diluted with ether. The mixture was
washed with 1M sodium carbonate solution and saturated sodium
chloride solution and the aqueous phase was back-extracted with
ether. The combined organic phases were dried over sodium sulfate
and the solvent was removed. The residue was dissolved in 8 ml of
dimethylformamide and, after the addition of 0.22 g of sodium
azide, stirred at 60.degree. for 7 hours. The mixture was diluted
with ether and extracted twice with water and once with saturated
sodium chloride solution. The aqueous phase was back-extracted with
ether and the combined organic phases were dried over sodium
sulfate. The solvent was removed and the residue was
chromatographed over 12 g of silica gel with toluene. There was
obtained 0.4 g (73.5%) of
(S)-1-(2-azido-propyl)-4-chloro-5-fluoroindole as a colourless
oil.
c) A suspension of 40 mg of platinum oxide in 8 ml of ethanol was
stirred under a hydrogen atmosphere for half an hour and
subsequently treated with a solution of 0.4 g of
(S)-1-(2-azido-propyl)-4-chloro-5-fluoroindole in 8 ml of ethanol.
The reaction mixture was stirred at room temperature for 1 hour.
The catalyst was filtered off and washed with ethanol. The solution
was evaporated and the residue was dissolved in 46 ml of ether and
0.3 ml of methanol and treated with 180 mg of fumaric acid and
stirred overnight. The separated crystals were filtered off and
dried. There was obtained 0.48 g (83.8%) of
(S)-2-(4-chloro-5-fluoroindol-1-yl)-1-methyl-ethylamine fumarate
(1:1) as white crystals with m.p. 183.degree.-184.degree.
(dec.)
EXAMPLE 24
a) A suspension of 0.11 g of sodium hydride dispersion in 15 ml of
tetrahydrofuran was treated with 0.5 g of 4-chloro-5-fluoroindole
at 0.degree. and stirred at this temperature for 1 hour. After the
addition of 0.4 ml of (S)-methyloxirane the reaction mixture was
stirred at s room temperature for 48 hours and subsequently treated
with water. The mixture was diluted with ether, washed with water
and with saturated sodium chloride solution and the organic phase
was dried over sodium sulfate. After removal of the solvent the
residue was chromatographed over 30 g of silica gel with
toluene-ethyl acetate (33:1). There was obtained 0.53 g (78.9%) of
(S)-1-(4-chloro-5-fluoro-indol-1-yl)-propan-2-ol as a yellow
oil.
b) A solution of 0.52 g of
(S)-1-(4-chloro-5-fluoro-indol-1-yl)-propan-2-ol in 11 ml of
dichloromethane was treated with 0.97 ml of triethylamine and
cooled to 0.degree.. 0.36 ml of methanesulfonyl chloride was added
dropwise to this solution and the reaction mixture was stirred for
one hour. The mixture was diluted with ether. The mixture was
washed with 1M sodium carbonate solution and saturated sodium
chloride solution and the aqueous phase was back-extracted with
ether. The combined organic phases were dried over sodium sulfate
and the solvent was removed. The residue was dissolved in 8 ml of
dimethylformamide and, after the addition of 0.22 g of sodium
azide, stirred at 60.degree. for 7 hours. The mixture was diluted
with ether and extracted twice with water and once with saturated
sodium chloride solution. The aqueous phase was back-extracted with
ether and the combined organic phases were dried over sodium
sulfate. The solvent was removed and the residue was
chromatographed over 12 g of silica gel with toluene. There was
obtained 0.4 g (70%) of
(R)-1-(2-azido-propyl)-4-chloro-5-fluoroindole as a colourless
oil.
c) A suspension of 40 mg of platinum oxide in 8 ml of ethanol was
stirred under a hydrogen atmosphere for half an hour and
subsequently treated with a solution of 0.4 g of
(R)-1-(2-azido-propyl)-4-chloro-5-fluoroindole in 8 ml of ethanol.
The reaction mixture was stirred at room temperature for 1 hour.
The catalyst was filtered off and washed with ethanol. The solution
was evaporated and the residue was dissolved in 46 ml of ether and
0.3 ml of methanol and treated with 180 ml of fumaric acid and
stirred overnight. The separated crystals were filtered off and
dried. There was obtained 0.48 g (83.8%) of
(R)-2-(4-chloro-5-fluorindol-1-yl)-1-methyl-ethylamine fumarate
(1:1) as white crystals with m.p. 186.degree.-187.degree.
(dec.)
EXAMPLE 25
a) A suspension of 0.26 g of sodium hydride dispersion in 35 ml of
tetrahydrofuran was treated with 0.95 g of 5-methylindole at
0.degree. and stirred at this temperature for 1 hour. After the
addition of 1 ml of (RS)-methyloxirane the reaction mixture was
stirred at room temperature for 48 hours and subsequently treated
with water. The mixture was diluted with ether, washed with water
and with saturated sodium chloride solution and the organic phase
was dried over sodium sulfate. After removal of the solvent the
residue was chromatographed over 30 g of silica gel with
toluene-ethyl acetate (19:1). There was obtained 0.86 g (62.7%) of
(RS)-1-(5-methyl-indol-1-yl)-propan-2-ol as a yellow oil.
b) A solution of 0.86 g of (RS)-1-(5-methyl-indol-1-yl)-propan-2-ol
in 20 ml of dichloromethane was treated with 1.6 ml of
triethylamine and cooled to 0.degree.. 0.6 ml of methanesulfonyl
chloride was added dropwise to this solution and the reaction
mixture was stirred for 1 hour. The mixture was diluted with ether.
The mixture was washed with 1M sodium carbonate solution and
saturated sodium chloride solution and the aqueous phase was
back-extracted with ether. The combined organic phases were dried
over sodium sulfate and the solvent was removed. The residue was
dissolved in 20 ml of dimethylformamide and, after the addition of
0.6 g of sodium azide, stirred at 60.degree. for 7 hours. The
mixture was diluted with ether and extracted with water and
saturated sodium chloride solution. The aqueous phase was
back-extracted with ether and the combined organic phases were
dried over sodium sulfate. The solvent was removed and the residue
was chromatographed over 30 g of silica gel with toluene. There was
obtained 0.68g (71.6%) of (RS)-1-(2-azido-propyl)-5-methylindole as
a yellow oil.
c) A solution of 0.6 g of (RS)-1-(2-azido-propyl)-5-methylindole as
in 20 ml of ethanol was hydrogenareal over 50 mg of Pd-C (5%). The
catalyst was filtered off and washed with ethanol. The solution was
evaporated and the residue was dissolved in 90 ml of ether and
treated with 0.35 g of fumaric acid and stirred overnight. The
separated crystals were isolated and dried. There was obtained 0.83
g (87%) of (RS)-2-(5-methyl-indol-1-yl)-1-methyl-ethylamine
fumarate (1:1) as white crystals with m.p. 165.degree.-167.degree.
(dec.)
EXAMPLE 26
a) While cooling with an ice bath 1.35 g of sodium were dissolved
in 30 ml of methanol and subsequently a solution of 4.65 g of
3-chloro-4-fluorobenzaldehyde and 6.75 g of methyl azidoacetate in
10 ml of methanol were added within 20 min. The reaction mixture
was stirred at room temperature for 3 hours and then neutralized
with 2N HCl. The mixture was extracted with ethyl acetate, washed
with water and saturated sodium chloride solution and the organic
phase was dried over sodium sulfate. The solvent was removed and
the residue was chromatographed over 250 g of silica gel with
n-hexane-toluene 2:1. There were obtained 2.5 g (33%) of methyl
3-chloro-4-fluoro-a-azidocinnamate as yellow crystals with m.p.
72.degree.-74.degree..
b) A mixture of 2.38 g of methyl
3-chloro-4-fluoro-a-azido-cinnamate and 180 ml of xylene was heated
under reflux for 45 min. The solvent was removed. There were
obtained 2.04 g (quant.) of an almost 1:1 mixture of methyl
5-chloro-6-fluoro-indole-2-carboxylate and methyl
7-chloro-6-fluoro-indole-2-carboxylate as light yellow crystals
which was used in the next step without further purification.
c) A suspension of 2.04 g of an almost 1:1 mixture of methyl
5-chloro-6-fluoro-indole-2-carboxylate and methyl
7-chloro-6-fluoro-indole-2-carboxylate in 90 ml of ethanol and 45
ml of 2N sodium hydroxide solution was stirred at room temperature
for 1 hour. The alcohol was evaporated and the residue was treated
with 55 ml of 2N hydrochloric acid. The separated crystals were
isolated, washed with water and dried. There were obtained 1.92 g
(quant.) of an almost 1:1 mixture of
5-chloro-6-fluoro-indole-2-carboxylic acid and
7-chloro-6-fluoro-indole-2-carboxylic acid as yellow crystals.
d) A suspension of 1.92 g of an almost 1:1 mixture of
5-chloro-6-fluoro-indole-2-carboxylic acid and
7-chloro-6-fluoro-indole-2-carboxylic acid in 45 ml of diphenyl
ether was stirred at 260.degree. for 4 hours. The reaction mixture
was chromatographed over 100 g of silica gel with hexane and
hexane-toluene (3:1). There were obtained 0.6 g (39%) of
5-chloro-6-fluoroindole as light brown crystals with m.p.
88.degree.-90.degree. and 0.22 g (14%) of 7-chloro-6-fluoroindole
as a dark brown oil.
e) A suspension of 128 mg of sodium hydride dispersion in 8 ml of
tetrahydrofuran was treated with 0.5 7 g of 5-chloro-6-fluoroindole
at 0.degree. and stirred at this temperature for 1 hour. After the
addition of 0.48 ml of (R)-methyloxirane the reaction mixture was
stirred at room temperature for 48 hours and subsequently treated
with water. The mixture was diluted with ether, washed with water
and with saturated sodium chloride solution and the organic phase
was dried over sodium sulfate. After removing the solvent the
residue was chromatographed over 25 g of silica gel with
toluene-ethyl acetate (19:1). There was obtained 0.59 g (77%) of
(R)-1-(5-chloro-6-fluoro-indol-1-yl)-propan-2-ol as beige crystals
with m.p. 108.degree.-110.degree..
f) A solution of 0.S7 g of
(R)-1-(5-chloro-6-fluoro-indol-1-yl)-propan-2-ol in 12 ml of
dichloromethane was treated with 0.4 ml of triethylamine and cooled
to 0.degree.. 0.2 ml of methanesulfonyl chloride was added dropwise
to this solution and the reaction mixture was stirred for one hour.
The mixture was diluted with ether. The mixture was washed with 1M
sodium carbonate solution and saturated sodium chloride solution
and the aqueous phase was back-extracted with ether. The combined
organic phases were dried over sodium sulfate and the solvent was
removed. The residue was dissolved in 12 ml of dimethylformamide
and, after the addition of 0.32 g of sodium azide, stirred at
60.degree. for 7 hours. The mixture was diluted with ether and
extracted with water and saturated sodium chloride solution. The
aqueous phase was back-extracted with ether and the combined
organic phases were dried over sodium sulfate. The solvent was
removed and the residue was chromatographed over 15 g of silica gel
with toluene-n-hexane 3:1. There was obtained 0.58 g (92%) of
(S)-1-(2-azido-propyl)-5-chloro-6-fluoroindole as a colourless
oil.
g) A suspension of 57 mg of platinum oxide in 10 ml of ethanol was
stirred under a hydrogen atmosphere for half an hour and
subsequently treated with a solution of 0.57 g of
(S)-1-(2-azido-propyl)-5-chloro-6-fluoroindole in 10 ml of ethanol.
The reaction mixture was stirred at room temperature for 1 hour.
The catalyst was filtered off and washed with ethanol. The solution
was evaporated and the residue was dissolved in 70 ml of ether and
2 ml of methanol and treated with 262 mg of fumaric acid and
stirred overnight. The separated crystals were isolated and dried.
There was obtained 0.63 g (82%) of
(S)-2-(5-chloro-6-fluoroindol-1-yl)-1-methyl-ethylamine fumarate
(1:1) as white crystals with m.p. 159.degree.-161.degree.
(dec.)
EXAMPLE 27
a) A suspension of 45 mg of sodium hydride dispersion in 10 ml of
tetrahydrofuran was treated with 0.2 g of 7-chloro-6-fluoroindole
at 0.degree. and stirred at this temperature for 1 hour. After the
addition of 0.17 ml of (RS)-methyloxirane the reaction mixture was
stirred at room temperature for 4 days and subsequently treated
with water. The mixture was diluted with ether, washed with water
and with saturated sodium chloride solution and the organic phase
was dried over sodium sulfate. After removal of the solvent the
residue was chromatographed over 15 g of silica gel with
toluene-ethyl acetate (19:1). There was obtained 0.21 g (77.8%) of
(RS)-1-(7-chloro-6-fluoro-indol-1-yl)-propan-2-ol as white crystals
with m.p. 85.degree.-87.degree..
b) A solution of 0.2 g of
(RS)-1-(7-chloro-6-fluoro-indol-1-yl)-propan-2-ol in 4.5 ml of
dichloromethane was treated with 0.4 ml of methylamine and cooled
to 0.degree.. 0.14 ml of methanesulfonyl chloride was added
dropwise to this solution and the reaction mixture was stirred for
one hour. The mixture was diluted with ether. The mixture was
washed with 1M sodium carbonate solution and saturated sodium
chloride solution and the aqueous phase was back-extracted with
ether. The combined organic phases were dried over sodium sulfate
and the solvent was removed. The residue was dissolved in 6 ml of
dimethylformamide and, after the addition of 0.15 g of sodium
azide, stirred at 60.degree. for 7 hours. The mixture was diluted
with ether and extracted with water and saturated sodium chloride
solution. The aqueous phase was back-extracted with ether and the
combined organic phases were dried over sodium sulfate. The solvent
was removed and the residue was chromatographed over 10 g of silica
gel with toluene-n-hexane 1:1. There was obtained 0.17 g (80%) of
(RS)-1-(2-azido-propyl)-7-chloro-6-fluoroindole as a colourless
oH.
c) A suspension of 17 mg of platinum oxide in 4 ml of ethanol was
stirred under a hydrogen atmosphere for half an hour and
subsequently treated with a solution of 0.16 g of
(RS)-1-(2-azido-propyl)-7-chloro-6-fluoroindole in 4 ml of ethanol.
The reaction mixture was stirred at room temperature for 1 hour.
The catalyst was filtered off and washed with ethanol. The solution
was evaporated and the residue was dissolved in 20 ml of ether and
0.2 ml of methanol and treated with 74 mg of fumaric acid and
stirred overnight. The separated crystals were isolated and dried.
There was obtained 0.19 g (86.5%) of
(RS)-2-(7-chloro-6-fluoroindol-1-yl)-1-methyl-ethylamine fumarate
(1:1) as white crystals with m.p. 187.degree.-188.degree.
(dec.)
EXAMPLE 28
a) A suspension of 75 ml of sodium hydride dispersion in 15 ml of
tetrahydrofuran was treated with 0.33 g of 5-chloro-2-methylindole
at 0.degree. and stirred at this temperature for 1 hour. After the
addition of 0.28 ml of (RS)-methyloxirane the reaction mixture was
stirred at room temperature for 48 hours and subsequently treated
with water. The mixture was diluted with ether, washed with water
and with saturated sodium chloride solution and the organic phase
was dried over sodium sulfate. After removal of the solvent the
residue was chromatographed over 13 g of silica gel with
toluene-ethyl acetate (19:1). There was obtained 0.27 g (61.7%) of
(RS)-1-(5-chloro-2-methyl-indol-1-yl)-propan-2-ol as a yellow
oil.
b) A solution of 0.26 g of
(RS)-1-(5-chloro-2-methyl-indol-1-yl)-propan-2-ol in 6 ml of
dichloromethane was treated with 0.5 ml of triethylamine and cooled
to 0.degree.. 0.2 ml of methanesulfonyl chloride was added dropwise
to this solution and the reaction mixture was stirred for one hour.
The mixture was diluted with ether. The mixture was washed with 1M
sodium carbonate solution and saturated sodium chloride solution
and the aqueous phase was back-extracted with ether. The combined
organic phases were dried over sodium sulfate and the solvent was
removed. The residue was dissolved in 6 ml of dimethylformamide
and, after the addition of 0.15 g of sodium azide, stirred at
60.degree. for 7 hours. The mixture was diluted with ether and
extracted with water and saturated sodium chloride solution. The
aqueous phase was back-extracted with ether and the combined
organic phases were dried over sodium sulfate. The solvent was
removed and the residue was chromatographed over 10 g of silica gel
with toluene-n-hexane 1:1. There was obtained 0.17 g (58.6%) of
(RS)-1-(5-chloro-2-methyl-indol-1-yl)-propan-2-ol as a colourless
oil.
c) A suspension of 16 ml of platinum oxide in 4 ml of ethanol was
stirred under a hydrogen atmosphere for half an hour and
subsequently treated with a solution of 0.16 g of
(RS)-1-(5-chloro-2-methyl-indol-1-yl)-propan-2-ol in 4 ml of
ethanol. The reaction mixture was stirred at room temperature for 1
hour. The catalyst was filtered off and washed with ethanol. The
solution was evaporated and the residue was dissolved in 20 ml of
ether and 0.2 ml of methanol and treated with 74 ml of fumaric acid
and stirred overnight. The separated crystals were isolated and
dried. There was obtained 0.19 g (86.5%) of
(RS)-2-(5-chloro-2-methylindol-1-yl)-1-methyl-ethylamine fumarate
(1:1) as white crystals with m.p. 193.degree.-194.degree.
(dec.)
EXAMPLE 29
a) A suspension of 263 mg of sodium hydride dispersion in 35 ml of
tetrahydrofuran was treated with 0.94 g of 5-fluoroindole at
0.degree. and stirred at this temperature for 1 hour. After the
addition of 1.22 ml of (RS)-butylene oxide the reaction mixture was
stirred at room temperature for 96 hours and subsequently treated
with water. The mixture was diluted with ether, washed with water
and with saturated sodium chloride solution and the organic phase
was dried over sodium sulfate. After removal of the solvent the
residue was chromatographed over 60 g of silica gel with toluene.
There were obtained 1.2 g (83%) of
(RS)-5-fluoro-indol-1-yl)-butan-2-ol as a yellow oil.
b) A solution of 1.15 g of (RS)-5-fluoro-indol-1-yl)-butan-2-ol in
28 ml of dichloromethane was treated with 3 ml of triethylamine and
cooled to 0.degree.. 0.86 ml of methanesulfonyl chloride was added
dropwise to this solution and the reaction mixture was stirred for
one hour. The mixture was diluted with ether. The mixture was as
washed with 1M sodium carbonate solution and saturated sodium
chloride solution and the aqueous phase was back-extracted with
ether. The combined organic phases were dried over sodium sulfate
and the solvent was removed. The residue was dissolved in 28 ml of
dimethylformamide and, after the addition of 0.72 g of sodium
azide, stirred at 60.degree. for 15 hours. The mixture was diluted
with ether and extracted with water and saturated sodium chloride
solution. The aqueous phase was back-extracted with ether and the
combined organic phases were dried over sodium sulfate. The solvent
was removed and the residue was chromatographed over 34 g of silica
gel with toluene. There were obtained 1.21 g (94 %) of
(RS)-1-(3-azido-butyl)-5-fluoroindole as a yellowish oil.
c) A solution of 1.18 g of (RS)-1-(3-azido-butyl)-5-fluoroindole in
25 ml of ethanol was hydrogenated over 120 mg of Pd-C (5%). The
catalyst was filtered off and washed with ethanol. The solution was
evaporated and the residue was dissolved in 1S0 ml of ether and 3
ml of methanol and treated with 0.47 g of fumaric acid and stirred
overnight. The separated crystals were isolated and dried. There
were obtained 1.26 g (77%) of
(RS)-1-ethyl-2-(5-fluoroindol-1-yl)-ethylamine fumarate (1:1) as
white crystals with m.p. 169.degree.-171.degree. (dec.)
EXAMPLE 30
a) 10 ml of 50% potassium hydroxide solution were added dropwise at
2.degree.-4.degree. over a period of 10 min. to a solution of 4.4 g
of 2-propylacetoacetic ester in 26 ml of ethanol. 50 ml of
ice-water were added and the mixture was treated rapidly with a
diazonium salt solution which had been prepared as follows: 5 ml of
a 25% hydrochloric acid solution were added dropwise while cooling
with an ice bath to a solution of 2.4 ml of 4-fluoroaniline in 25
ml of ethanol. Subsequently, 3.4 ml of isopentyl nitrite were added
at 4.degree. within 10 min. The orange emulsion, which resulted
from the addition of the diazonium salt solution, was poured into
100 ml of water and extracted once with 100 ml of toluene and twice
with 50 ml of toluene each time. The combined organic phases were
dried over sodium surfate, filtered and concentrated to a volume of
50 ml. After boiling on a water separator for 30 min. a solution of
7.13 g of p-toluenesulfonic acid monohydrate in 50 ml of toluene
was added and the mixture was heated on a water separator for a
further hour. After cooling the mixture was extracted with 50 ml of
1N hydrochloric acid, 50 ml of 1N sodium hydroxide solution and 25
ml of saturated sodium chloride solution. The aqueous phases were
back-washed with 50 ml of toluene and the combined organic phases
were dried over sodium sulfate, filtered and evaporated. The
residue was chromatographed over 105 g of silica gel with toluene.
4.27 g (72.6%) of crude ethyl 3-ethyl-5-fluoroindole-2-carboxylate
were obtained. A sample was recrystailized from hexane and then
showed a m.p. of 111.degree.-113.degree..
b) A suspension of 1.4 g of ethyl
3-ethyl-5-fluoroindole-2-carboxylate in 30 ml of ethanol was
treated with 12 ml of 2N sodium hydroxide solution and stirred for
16 hours. Ethanol was evaporated and the reaction solution was
adjusted to pH 1 with 25% hydrochloric acid. The precipitate was
washed with water and dried. There were obtained 1.22 g (98%) of
crude 4-chloro-5-fluoroindole-2-carboxylic acid which was used
without further purification in the next step.
c) A suspension of 1.21 g of 3-ethyl-5-fluoroindole-2-carboxylic
acid in 16 ml of diphenyl ether was stirred at 260.degree. for 2
hours and, after cooling to 0.degree., diluted with 29 ml of
tetrahydrofuran. 218 mg of sodium hydride dispersion were added and
the mixture was stirred for one hour. Subsequently, 0.61 ml of
(R)-methyloxirane was added and the reaction mixture was stirred at
room temperature for 90 hours. The mixture was extracted with
diethyl ether, water and saturated sodium chloride solution and the
organic phase was dried over sodium sulfate. The solvent was
removed and the residue was chromatographed over 120 g of silica
gel with hexane-toluene (1:2) and subsequently with toluene-ethyl
acetate (9:1). 0.8 g (62%) of
(R)-1-(3-ethyl-5-fluoro-indol-1-yl)-propan-2-ol was obtained as
pale brown crystals with m.p. 65.degree.-67.degree..
d) A solution of 0.77 g of
(R)-1-(3-ethyl-5-fluoro-indol-1-yl)-propan-2-ol in 17 ml of
dichloromethane was treated with 1.9 ml of triethylamine and cooled
to 0.degree.. 0.54 ml of methanesulfonyl chloride was added
dropwise to this solution and the reaction mixture was stirred for
2 hours. The mixture was diluted with ether. The mixture was washed
with iM sodium carbonate solution and saturated sodium chloride
solution and the aqueous phase was back-extracted with ether. The
combined organic phases were dried over sodium sulfate and the
solvent was removed. The residue was dissolved in 17 ml of
dimethylformamide and, after the addition of 0.45 g of sodium
azide, stirred at 60.degree. overnight. The mixture was diluted
with ether and extracted with water and saturated sodium chloride
solution. The aqueous phase was back-extracted with ether and the
combined organic phases were dried over sodium sulfate. The solvent
was removed and the residue was chromatographed over 15 g of silica
gel with toluene-hexane (2:1). 0.78 g (91%) of
(S)-1-(2-azido-propyl)-3-ethyl-5-fluoroindole was obtained as a
yellow oil.
e) A suspension of 76 mg of platinum oxide in 15 ml of ethanol was
stirred under a hydrogen atmosphere for half an hour and
subsequently treated with a solution of 0.76 g of
(S)-1-(2-azido-propyl)-3-ethyl-5-fluoroindole in 15 ml of ethanol.
The reaction mixture was stirred at room temperature for 20 hours.
The catalyst was filtered off and washed with ethanol. The solution
was evaporated and the residue was dissolved in 90 ml of ether and
1.9 ml of methanol and treated with 358 mg of fumaric acid and
stirred overnight. The separated crystals were isolated and dried.
0.91 g (88%) of
(S)-2-(2-ethyl-5-fluoroindol-1-yl)-1-methyl-ethylamine fumarate
(1:1) was obtained as white crystals with m.p.
164.degree.-166.degree. (dec.).
EXAMPLE 31
a) A suspension of 0.16 g of sodium hydride dispersion in 22 ml of
tetrahydrofuran was treated with 0.38 g of
4-isopropyl-5-fluoroindole at 0.degree. and stirred at this
temperature for I hour. After the addition of 0.6 ml of
(R)-methyloxirane the reaction mixture was stirred at room
temperature for 120 hours and subsequently treated with water. The
mixture was diluted with ether, washed with water and saturated
sodium chloride solution and the organic phase was dried over
sodium sulfate. After removal of the solvent the residue was
chromatographed over 25 g of silica gel with toluene-ethyl acetate
(19:1). 0.41 g (81%) of
(R)-1-(4-isopropyl-5-fluoro-indol-1-yl)-propan-2-ol was obtained as
a yellow oil.
b) A solution of 0.41 g of
(R)-1-(4-isopropyl-5-fluoro-indol-1-yl)-propan-2-ol in 10 ml of
dichloromethane was treated with 0.74 ml of triethylamine and
cooled to 0.degree.. 0.27 ml of methanesulfonyl chloride was added
dropwise to this solution and the reaction mixture was stirred for
2 hours. The mixture was diluted with ether. The mixture was washed
with 1M sodium carbonate solution and saturated sodium chloride
solution and the aqueous phase was back-extracted with ether. The
combined organic phases were dried over sodium sulfate and the
solvent was removed. The residue was dissolved in 10 ml of
dimethylformamide and, after the addition of 0.22 g of sodium
azide, stirred at 60.degree. overnight. The mixture was diluted
with ether and extracted with water and saturated sodium chloride
solution. The aqueous phase was back-extracted with ether and the
combined organic phases were dried over sodium sulfate. The solvent
was removed and 0.4 g (90%) of
(S)-1-(2-azido-propyl)-4-isopropyl-5-fluoroindole was obtained as a
yellow oil.
c) A solution of 0.4 g of
(S)-1-(2-azido-propyl)-4-isopropyl-5-fluoroindole in 15 ml of
ethanol was hydrogenated over 40 mg of Pd-C (5%). The catalyst was
filtered off and washed with ethanol. The solution was evaporated
and the residue was dissolved in 45 ml of ether and 2 ml of
methanol and treated with 0.17 g of fumaric acid and stirred
overnight. The separated crystals were isolated and dried. 0.43 g
(80%) of (S)-2-(4-isopropyl-5-fluoroindol-1-yl)-1-methyl-ethylamine
fumarate (1:1) was obtained as white crystals with m.p.
166.degree.-167.degree. (dec.).
EXAMPLE 32
a) A suspension of 0.05 g of sodium hydride dispersion in 10 ml of
tetrahydrofuran was treated with 0.23 g of
6-isopropyl-5-fluoroindole at 0.degree. and stirred at this
temperature for 1 hour. After the addition of 0.18 ml of
(R)-methyloxirane the reaction mixture was stirred at room
temperature for 70 hours and subsequently treated with water. The
mixture was diluted with ether, washed with water and with
saturated sodium chloride solution and the organic phase was dried
over sodium sulfate. After removal of the solvent the residue was
chromatographed over 15 g of silica gel with toluene-ethyl acetate
(19:1). 0.08 g (27%) of
(R)-1-(6-isopropyl-5-fluoro-indol-1-yl)-propan-2-ol was obtained as
a yellow oil.
b) A solution of 0.08 g of
(R)-1-(6-isopropyl-5-fluoro-indol-1-yl)-propan-2-ol in 1.7 ml of
dichloromethane was treated with 0.14 ml of triethylamine and
cooled to 0.degree.. 0.05 ml of methanesulfonyl chloride was added
dropwise to this solution and the reaction mixture was stirred for
2 hours. The mixture was diluted with ether. The mixture was washed
with 1M sodium carbonate solution and saturated sodium chloride
solution and the aqueous phase was back-extracted with ether. The
combined organic phases were dried over sodium sulfate and the
solvent was removed. The residue was dissolved in 1.7 ml of
dimethylformamide and, after the addition of 0.04 g of sodium
azide, stirred at 60.degree. overnight. The mixture was diluted
with ether and extracted with water and saturated sodium chloride
solution. The aqueous phase was back-extracted with ether and the
combined organic phases were dried over sodium sulfate. The solvent
was removed and the residue was chromatographed over 10 g of silica
gel with toluene-hexane (1:1). 0.06 g (75%) of
(S)-1-(2-azido-propyl)-6-isopropyl-5-fluoroindole was obtained as a
colourless oil.
c) A solution of 0.05 g of
(S)-1-(2-azido-propyl)-6-isopropyl-5-fluoroindole in 2 ml of
ethanol was hydrogenated over 5 mg of Pd-C (5%). The catalyst was
filtered off and washed with ethanol. The solution was evaporated
and the residue was dissolved in 6 ml of ether and treated with
0.02 g of fumaric acid and stirred overnight. The separated
crystals were isolated and dried. 0.07 g (97%) of
(S)-2-(6-isopropyl-5-fluoroindol-1-yl)-1-methyl-ethylamine fumarate
(1:1.2) was obtained as while crystals with m.p.
168.degree.-169.degree. (dec.).
EXAMPLE 33
a) A suspension of 1.16 g of
6-chloro-5-fluoro-3-ethyl-indole-2-carboxylic acid in 16 ml of
diphenyl ether was stirred at 260.degree. for 4 hours and, after
cooling to 0.degree., diluted with 24 ml of tetrahydrofuran. 180 mg
of sodium hydride dispersion were added and the mixture was stirred
for one hour. Subsequently, 0.5 ml of (R)-methyloxirane was added
and the reaction mixture was stirred at room temperature for 112
hours. The mixture was extracted with diethyl ether, water and
saturated sodium chloride solution and the organic phase was dried
over sodium sulfate. The solvent was removed and the residue was
chromatographed over 120 g of silica gel with hexane-toluene (1:2)
and subsequently with toluene-ethyl acetate (9:1). 0.97 g (79%) of
(R)-1-(6-chloro-5-fluoro-3-ethylindol-1-yl)-propan-2-ol was
obtained as pale brown crystals with m.p.
112.degree.-114.degree..
b) A solution of 0.93 g of
(R)-1-(6-chloro-5-fluoro-3-ethylindol-1-yl)-propan-2-ol in 18 ml of
dichloromethane was treated with 2 of triethylamine and cooled to
0.degree.. 0.57 ml of methanesulfonyl chloride was added dropwise
to this solution and the reaction mixture was stirred for 2 hours.
The mixture was diluted with ether. The mixture was washed with 1M
sodium carbonate solution and saturated sodium chloride solution
and the aqueous phase was back-extracted with ether. The combined
organic phases were dried over sodium sulfate and the solvent was
removed. The residue was dissolved in 18 ml of dimethylformamide
and, after the addition of 0.47 g of sodium azide, stirred at
60.degree. overnight. The mixture was diluted with ether and
extracted with water and saturated sodium chloride solution. The
aqueous phase was back-extracted with ether and the combined
organic phases were dried over sodium sulfate. The solvent was
removed and the residue was chromatographed over 20 g of silica gel
with toluene-hexane (2:1). 1 g (97%) of
(S)-1-(2-azido-propyl)-6-chloro-5-fluoro-3-ethylindole was obtained
as a yellow oil.
c) A suspension of 100 mg of platinum oxide in 17 ml of ethanol was
stirred under a hydrogen atmosphere for half an hour and
subsequently treated with a solution of 0.97 g of
(S)-1-(2-azido-propyl)-6-chloro-5-fluoro-3-ethylindole in 17 ml of
ethanol. The reaction mixture was stirred at room temperature for
15 hours. The catalyst was filtered off and washed with ethanol.
The solution was evaporated and the residue was dissolved in 100 ml
of ether and 2 ml of methanol and treated with 400 mg of fumaric
acid and stirred overnight. The separated crystals were isolated
and dried. 1.18 g (92%) of
(S)-2-(6-chloro-5-fluoro-3-ethylindol-1-yl)-1-methyl-ethylamine
fumarate (1:1) were obtained as white crystals with m.p.
172.degree.-173.degree. (dec.).
EXAMPLE 34
a) A suspension of 1.2 g of
4-chloro-5-fluoro-3-ethyl-indole-2-carboxylic acid in 16 ml of
diphenyl ether was stirred at 260.degree. for 4 hours and, after
cooling to 0.degree., diluted with 24 ml of tetrahydrofuran. 186 mg
of sodium hydride dispersion were added and the mixture was stirred
for one hour. Subsequently, 0.5 ml of (R)-methyloxirane was added
and the reaction mixture was stirred at room temperature for 114
hours. The mixture was extracted with diethyl ether, water and
saturated sodium chloride solution and the organic phase was dried
over sodium surfate. The solvent was removed and the residue was
chromatographed over 120 g of silica gel with hexane-toluene (1:2)
and subsequently with toluene-ethyl acetate (9:!). 102 g (80%) of
(R)-1-(4-chloro-5-fluoro-3-ethylindol-1-yl)-propan-2-ol were
obtained as pale brown crystals with m.p.
87.degree.-88.degree..
b) A solution of 0.98 g of
(R)-1-(4-chloro-5-fluoro-3-ethylindol-1-yl)-propan-2-ol in 19 ml of
dichloromethane was treated with 2 ml of triethylamine and cooled
to 0.degree.. 0.6 ml of methanesulfonyl chloride was added dropwise
to this solution and the reaction mixture was stirred for 2 hours.
The mixture was diluted with ether. The mixture was washed with 1M
sodium carbonate solution and saturated sodium chloride solution
and the aqueous phase was back-extracted with ether. The combined
organic phases were dried over sodium sulfate and the solvent was
removed. The residue was dissolved in 19 ml of dimethylformamide
and, after the addition of 0.5 g of sodium azide, stirred at
60.degree. overnight. The mixture was diluted with ether and
extracted with water and saturated sodium chloride solution. The
aqueous phase was back-extracted with ether and the combined
organic phases were dried over sodium sulfate. The solvent was
removed and the residue was chromatographed over 20 g of silica gel
with toluene-hexane (2:1). 1.04 g (96%) of
(S)-1-(2-azido-propyl)-4-chloro-5-fluoro-3-ethylindole were
obtained as a yellow oil.
c) A suspension of 100 mg of platinum oxide in 18 ml of ethanol was
stirred under a hydrogen atmosphere for half an hour and
subsequently treated with a solution of 1.02 g of
(S)-1-(2-azido-propyl)-4-chloro-5-fluoro-3-ethylindole in 18 ml of
ethanol. The reaction mixture was stirred at room temperature for 4
hours. The catalyst was filtered off and washed with ethanol. The
solution was evaporated and the residue was dissolved in 100 ml of
ether and 2 ml of methanol and treated with 416 mg of fumaric acid
and stirred overnight. The separated crystals were isolated and
dried. 1.23 g (91%) of
(S)-2-(4-chloro-5-fluoro-3-ethylindol-1-yl)-1-methyl-ethylamine
fumarate (1:1) were obtained as white crystals with m.p.
178.degree.-181.degree. (dec.).
EXAMPLE 35
a) A suspension of 1.16 g of 5-fluoro-3-methyl-indole-2-carboxylic
acid in 16 ml of diphenyl ether was stirred at 260.degree. for 5
hours and, after cooling to 0.degree., diluted with 30 ml of
tetrahydrofuran. 225 mg of sodium hydride dispersion were added and
the mixture was stirred for one hour. Subsequently, 0.63 ml of
(R)-methyloxirane was added and the reaction mixture was stirred at
room temperature for 90 hours. The mixture was extracted with
diethyl ether, water and saturated sodium chloride solution and the
organic phase was dried over sodium surfate. The solvent was
removed and the residue was chromatographed over 120 g of silica
gel with hexane-toluene (1:1) and subsequently with toluene-ethyl
acetate (19:1). 0.87 g (70%) of
(R)-1-(5-fluoro-3-methylindol-1-yl)-propan-2-ol was obtained as a
pale brown oil.
b) A solution of 0.84 g of
(R)-1-(5-fluoro-3-methylindol-1-yl)-propan-2-ol in 20 ml of
dichloromethane was treated with 2 ml of triethylamine and cooled
to 0.degree.. 0.63 ml of methanesulfonyl chloride was added
dropwise to this solution and the reaction mixture was stirred for
2 hours. The mixure was diluted with ether. The mixture was washed
with 1M sodium carbonate solution and saturated sodium chloride
solution and the aqueous phase was back-extracted with ether. The
combined organic phases were dried over sodium sulfate and the
solvent was removed. The residue was dissolved in 20 ml of
dimethylformamide and, after the addition of 0.52 g of sodium
azide, stirred at 60.degree. overnight. The mixture was diluted
with ether and extracted with water and saturated sodium chloride
solution. The aqueous phase was back-extracted with ether and the
combined organic phases were dried over sodium sulfate. The solvent
was removed and the residue was chromatographed over 90 g of silica
gel with toluene-hexane (1:1). 0.87 g (90%) of
(S)-1-(2-azido-propyl)-5-fluoro-3-methylindole was obtained as a
colourless oil.
c) A solution of 0.85 g of
(S)-1-(2-azido-propyl)-5-fluoro-3-methylindole in 37 ml of ethanol
was hydrogenated over 85 mg of Pd-C (5%). The catalyst was filtered
off and washed with ethanol. The solution was evaporated and the
residue was dissolved in 100 ml of ether and 5 ml of methanol and
treated with 0.42 g of fumaric acid and stirred overnight. The
separated crystals were isolated and dried. 1.02 g (86%) of
(S)-1-methyl-2-(5-fluoro-3-methylindol-1-yl)-ethylamine fumarate
(1:1) were obtained as white crystals with m.p.
167.degree.-168.degree. (dec.).
EXAMPLE 36
a) A suspension of 0.07 g of sodium hydride dispersion in 10 ml of
tetrahydrofuran was treated with 0.33 g of
6-chloro-5-fluoro-3-methylindole at 0.degree. and stirred as this
temperature for 1 hour. After the addition of 0.19 ml of
(R)-methyloxirane the reaction mixture was stirred at room
temperature for 17 hours and subsequently treated with water. The
mixture was diluted with ether, washed with water and with
saturated sodium chloride solution and the organic phase was dried
over sodium sulfate. After removal of the solvent the residue was
chromatographed over 20 g of silica gel with toluene-ethyl acetate
(9:1). 0.22 g (50%) of
(R)-1-(6-chloro-5-fluoro-3-methylindol-1-yl)-propan-2-ol was
obtained as a yellow oil.
b) A solution of 0.2 g of
(R)-1-(6-chloro-5-fluoro-3-methylindol-1-yl)-propan-2-ol in 4 ml of
dichloromethane was treated with 0.47 mg of triethylamine and
cooled to 0.degree.. 0.13 ml of methanesulfonyl chloride was added
dropwise to this solution and the reaction mixture was stirred for
5 hours. The mixture was diluted with ether. The mixture was washed
with 1M sodium carbonate solution and saturated sodium chloride
solution and the aqueous phase was back-extracted with ether. The
combined organic phases were dried over sodium sulfate and the
solvent was removed. The residue was dissolved in 4 ml of
dimethylforrnamide and, after the addition of 0.1 g of sodium
azide, stirred at 60.degree. overnight. The mixture was diluted
with ether and extracted with water and saturated sodium chloride
solution. The aqueous phase was back-extracted with ether and the
combined organic phases were dried over sodium sulfate. The solvent
was removed and the residue was chromatographed over 4.5 g of
silica gel with toluene-hexane (2:1). 0.2 g (93%) of
(S)-1-(2-azido-propyl)-6-chloro-5-fluoro-3-methylindole was
obtained as a colourless oil.
c) A suspension of 20 mg of platinum oxide in 3.6 ml of ethanol was
stirred under a hydrogen atmosphere for half an hour and
subsequently treated with a solution of 0.19 g of
(S)-1-(2-azido-propyl)-6-chloro-5-fluoro-3-methylindole in 3.6 ml
of ethanol. The reaction mixture was stirred at room temperature
for 17 hours. The catalyst was filtered off and washed with
ethanol. The solution was evaporated and the residue was dissolved
in 20 ml of ether and 0.4 ml of methanol and treated with 76 mg of
fumaric acid and stirred overnight. The separated crystals were
isolated and dried. 0.18 g (74%) of
(S)-2-(6-chloro-5-fluoro-3-methylindol-1-yl)-1-methyl-ethylamine
fumarate (1:1) was obtained as white crystals with m.p.
174.degree.-176.degree. (dec.).
EXAMPLE 37
a) A suspension of 1.98 g of
5-fluoro-3-methoxy-4-methylindole-2-carboxylic acid in 16 ml of
diphenyl ether was stirred at 260.degree. for 0.5 hour and, after
cooling to 0.degree., diluted with 44 ml of tetrahydrofuran. 0.33 g
of sodium hydride dispersion was added and the mixture was stirred
for one hour. Subsequently, 1 ml of (R)-methyloxirane was added and
the reaction mixture was stirred at room temperature for 90 hours.
The mixture was extracted with diethyl ether, water and saturated
sodium chloride solution and the organic phase was dried over
sodium surfate. The solvent was removed and the residue was
chromatographed over 120 g of silica gel with toluene and
toluene-ethyl acetate (9:1). 1.69 g (80%) of
(R)-1-(5-fluoro-3-methoxy-4-methylindol-1-yl)-propan-2-ol were
obtained as a pale brown oil.
b) A solution of 1.64 g of
(R)-1-(5-fluoro-3-methoxy-4-methylindol-1-yl)-propan-2-ol in 35 ml
of dichloromethane was treated with 3.85 ml of triethylamine and
cooled to 0.degree.. 1.07 ml of methanesulfonyl chloride were added
dropwise to this solution and the reaction mixture was stirred for
2 hours. The mixture was diluted with ether. The mixture was washed
with 1M sodium carbonate solution and saturated sodium chloride
solution and the aqueous phase was back-extracted with ether. The
combined organic phases were dried over sodium sulfate and the
solvent was removed. The residue was dissolved in 30 ml of
dimethylformamide and, after the addition of 0.82 g of sodium
azide, stirred at 60.degree. for 3 hours. The mixture was diluted
with ether and extracted with water and saturated sodium chloride
solution. The aqueous phase was back-extracted with ether and the
combined organic phases were dried over sodium sulfate. The solvent
was removed and the residue was chromatographed over 50 g of silica
gel with toluene. 1.82 g (77%) of (77 %)
(S)-1-(2-azido-propyl)-5-fluoro-3-methoxy-4-methylindole were
obtained as a yellow oil.
c) A suspension of 127 mg of platinum oxide in 24 ml of ethanol was
stirred under a hydrogen atmosphere for half an hour and
subsequently treated with a solution of 1.27 g of
(S)-1-(2-azido-propyl)-5-fluoro-3-methoxy-4-methylindole in 3.6 ml
of ethanol. The reaction mixture was stirred at room temperature
for 15 hours. The catalyst was filtered off and washed with
ethanol. The solution was evaporated and the residue was dissolved
in 145 ml of ether and 3 ml of methanol and treated with 0.56 g of
fumaric acid and stirred overnight. The separated crystals were
isolated and dried. 1.5 g (88%) of
(S)-2-(5-fluoro-3-methoxy-4-methylindol-1-yl)-1-methyl-ethylamine
fumarate (1:1) were obtained as white crystals with m.p.
173.degree.-176.degree. (dec.).
EXAMPLE 38
a) 1.4 g of 3-methoxy-4-methylindole-2-carboxylic acid were heated
to 160.degree. for 5 min. while gassing with argon and, after
cooling to 0.degree., diluted with 34 ml of tetrahydrofuran. 0.25 g
of sodium hydride dispersion was added and the mixture was stirred
for one hour. Subsequently, 0.7 ml of (R)-methyloxirane was added
and the reaction mixture was stirred at room temperature for 60
hours. The mixture was extracted with diethyl ether, water and
saturated sodium chloride solution and the organic phase was dried
over sodium sulfate. The solvent was removed and the residue was
chromatographed over 60 g of silica gel with toluene-ethyl acetate
(9:1). 0.8 g (54%) of
(R)-1-(5-fluoro-3-methoxy-4-methylindol-1-yl)-propan-2-ol was
obtained as a pale brown oil.
b) A solution of 0.8 g of
(R)-1-(5-fluoro-3-methoxy-4-methylindol-1-yl)-propan-2-ol in 18 ml
of dichloromethane was treated with 2 ml of triethylamine and
cooled to 0.degree.. 0.5 ml of methanesulfonyl chloride was added
dropwise to this solution and the reaction mixture was stirred for
1 hour. The mixture was diluted with ether. The mixture was washed
with 1M sodium carbonate solution and saturated sodium chloride
solution and the aqueous phase was back-extracted with ether. The
combined organic phases were dried over sodium sulfate and the
solvent was removed. The residue was dissolved in 18 ml of
dimethylformamide and, after the addition of 0.43 g of sodium
azide, stirred at 60.degree. for 3 hours. The mixture was diluted
with ether and extracted with water and saturated sodium chloride
solution. The aqueous phase was back-extracted with ether and the
combined organic phases were dried over sodium sulfate. The solvent
was removed and the residue was chromatographed over 22 g of silica
gel with toluene-hexane (1:1). 0.46 g (57%) of
(S)-1-(2-azido-propyl)-3-methoxy-4-methylindole was obtained as a
yellow oil.
c) A suspension of 45 mg of platinum oxide in 9 ml of ethanol was
stirred under a hydrogen atmosphere for half an hour and
subsequently treated with a solution of 0.45 g of
(S)-1-(2-azido-propyl)-3-methoxy-4-methylindole in 9 ml of ethanol.
The reaction mixture was stirred at room temperature for 3 hours.
The catalyst was filtered off and washed with ethanol. The solution
was evaporated and the residue was dissolved in 55 ml of ether and
1 ml of methanol and treated with 214 mg of fumaric acid and
stirred overnight. The separated crystals were isolated and dried.
0.53 g (86%) of
(S)-2-(3-methoxy-4-methylindol-1-yl)-1-methyl-ethylamine fumarate
(1:1) was obtained as pale yellow crystals with m.p.
161.degree.-162.degree. (dec.).
EXAMPLE A
Tablets of the following composition were manufactured in the usual
manner:
______________________________________ mg/tablet
______________________________________ Active ingredient 100 Powd.
lactose 95 White corn starch 35 Polyvinylpyrrolidone 8 Na
carboxymethylstarch 10 Magnesium stearate 2 Tablet weight 250
______________________________________
EXAMPLE B
Tablets of the following composition are manufactured in the usual
manner:
______________________________________ mg/tablet
______________________________________ Active ingredient 200 Powd.
lactose 100 White corn starch 64 Polyvinylpyrrolidone 12 Na
carboxymethylstarch 20 Magnesium stearate 4 Tablet weight 400
______________________________________
EXAMPLE C
Capsules of the following composition are manufactured:
______________________________________ mg/capsule
______________________________________ Active ingredient 50 Cryst.
lactose 60 Microcrystalline cellulose 34 Talc 5 Magnesium stearate
1 Capsule fill weight 150
______________________________________
The active ingredient having a suitable particle size, the
crystalline lactose and the microcrystalline cellulose are
homogeneously mixed with one another, sieved and thereafter talc
and magnesium stearate are admixed. The finished mixture is filled
into hard gelatine capsules of suitable size.
* * * * *